Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001754.4(RUNX1):c.1338C>T (p.Leu446=)

CA10014185

561227 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 137090bc-e630-47fc-95fd-c500c7dbe2f4
Approved on: 2022-07-07
Published on: 2022-07-07

HGVS expressions

NM_001754.4:c.1338C>T
NM_001754.4(RUNX1):c.1338C>T (p.Leu446=)
NC_000021.9:g.34792240G>A
CM000683.2:g.34792240G>A
NC_000021.8:g.36164537G>A
CM000683.1:g.36164537G>A
NC_000021.7:g.35086407G>A
NG_011402.2:g.1197472C>T
ENST00000675419.1:c.1338C>T
ENST00000300305.7:c.1338C>T
ENST00000344691.8:c.1257C>T
ENST00000399240.5:c.1065C>T
ENST00000437180.5:c.1338C>T
ENST00000482318.5:c.*928C>T
NM_001001890.2:c.1257C>T
NM_001001890.3:c.1257C>T
NM_001754.5:c.1338C>T
NM_001754.5(RUNX1):c.1338C>T (p.Leu446=)
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Benign

The Expert Panel has overridden the computationally generated classification - "Likely Benign"
Met criteria codes 4
BP4 BP2 BP7 BS1
Not Met criteria codes 22
BP3 BP1 BP5 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2 PVS1 PM1 PM4 PM5 PM3 PM6 PM2 BA1 BS2 BS4 BS3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
This c.1338C>T (p.Leu446=) synonymous variant, located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP score = -0.004008 in GRCh38), is not predicted to have any splicing impact per SpliceAI (BP4+BP7). In addition, the variant is present in gnomAD at an allele frequency between 0.015% and 0.15% in a general continental population (South Asian subpopulation: 0.03506% in v2 and 0.1449% in v3) with >5 variant alleles and a minimum of 2000 total alleles (BS1) and was found in homozygosity in the population database (BP2). In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP2, BP4, and BP7.
Met criteria codes
BP4
No donor/acceptor gains or losses predicted (SpliceAI Δ score <= 0.2).
BP2
Variant is found in one South Asian homozygote in gnomAD v.3.1.1, who is between 65-70 years of age.
BP7
Synonymous variant located at a non-conserved nucleotide (PhyloP score = -0.004008 in GRCh38). SpliceAI does not predict any impact.
BS1
Variant is present in >=5 alleles in the South Asian population (has required minimum of 2000 alleles) with an MAF of 0.03506% (v2.1.1) or 0.1449% (v3.1.1), which is within the BS1 thresholds (0.015%-0.15%). - gnomAD v2.1.1: ALL: 0.007875% (11/139684) - SAS: 0.03506% (8/22820) - EAS: 0.008767% (1/11406) - AMR: 0.008026% (2/24918) - gnomAD v3.1.1: ALL: 0.007895% (12/151996) - SAS: 0.1449% (5+2/4832) - OTH: 0.04785% (1/2090) - AMR (0.01309% (2/15274) - NFE: 0.002944% (2/67942)
Not Met criteria codes
BP3
Not applicable
BP1
Not applicable
BP5
Not applicable
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No literature found in HGMD, Google+Google Scholar searches, or COSMIC.
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Not applicable
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No donor/acceptor gains or losses predicted with SpliceAI Δ score >= 0.38.
PP2
Not applicable
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
Not applicable
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
Variant is present in >=5 alleles in the South Asian population (has required minimum of 2000 alleles) with an MAF of 0.03506% (v2.1.1) or 0.1449% (v3.1.1), which is within the BS1 thresholds (0.015%-0.15%). - gnomAD v2.1.1: ALL: 0.007875% (11/139684) - SAS: 0.03506% (8/22820) - EAS: 0.008767% (1/11406) - AMR: 0.008026% (2/24918) - gnomAD v3.1.1: ALL: 0.007895% (12/151996) - SAS: 0.1449% (5+2/4832) - OTH: 0.04785% (1/2090) - AMR (0.01309% (2/15274) - NFE: 0.002944% (2/67942)
BA1
Variant is present in >=5 alleles in the South Asian population (has required minimum of 2000 alleles) with an MAF of 0.03506% (v2.1.1) or 0.1449% (v3.1.1), which is within the BS1 thresholds (0.015%-0.15%). - gnomAD v2.1.1: ALL: 0.007875% (11/139684) - SAS: 0.03506% (8/22820) - EAS: 0.008767% (1/11406) - AMR: 0.008026% (2/24918) - gnomAD v3.1.1: ALL: 0.007895% (12/151996) - SAS: 0.1449% (5+2/4832) - OTH: 0.04785% (1/2090) - AMR (0.01309% (2/15274) - NFE: 0.002944% (2/67942)
BS2
Not applicable
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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