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]
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Variant: NM_001754.5(RUNX1):c.648C>T (p.Pro216=)

CA10014386

239051 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f1b97082-d2b4-49f2-9fd8-2618a3a9f6a3
Approved on: 2022-07-05
Published on: 2022-07-05

HGVS expressions

NM_001754.5:c.648C>T
NM_001754.5(RUNX1):c.648C>T (p.Pro216=)
NC_000021.9:g.34834567G>A
CM000683.2:g.34834567G>A
NC_000021.8:g.36206864G>A
CM000683.1:g.36206864G>A
NC_000021.7:g.35128734G>A
NG_011402.2:g.1155145C>T
ENST00000675419.1:c.648C>T
ENST00000300305.7:c.648C>T
ENST00000344691.8:c.567C>T
ENST00000358356.9:c.567C>T
ENST00000399237.6:c.612C>T
ENST00000399240.5:c.532+24907C>T
ENST00000437180.5:c.648C>T
ENST00000469087.1:n.184C>T
ENST00000482318.5:c.*238C>T
NM_001001890.2:c.567C>T
NM_001122607.1:c.567C>T
NM_001754.4:c.648C>T
NM_001001890.3:c.567C>T
NM_001122607.2:c.567C>T
More

Benign

The Expert Panel has overridden the computationally generated classification - "Likely Benign"
Met criteria codes 3
BS1 BP7 BP4
Not Met criteria codes 23
BA1 BS4 BS3 BS2 BP5 BP2 BP3 BP1 PS4 PS2 PS1 PS3 PP4 PP1 PP3 PP2 PM5 PM3 PM1 PM4 PM6 PM2 PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
The c.648C>T (p.Pro216=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -2.75191 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species (BP7). The highest population minor allele frequency for this variant in gnomAD v3 is 0.05079% (21/41346 alleles) in the African/African American population, which is higher than the ClinGen Myeloid Malignancy VCEP threshold of 0.015% (BS1). The variant also has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BS1, BP4, and BP7
Met criteria codes
BS1
gnomAD (v2): ALL: 0.01383% (39/281942) - NFE: 0.01945% (25/128566) - AFR: 0.03609% (9/24940) - AMR: 0.01129% (4/35426) - FIN: 0.004022% (1/24862) gnomAD (v3): ALL: 0.02040% (31/151992) - NFE: 0.01029% (7/68012) - AFR: 0.05079% (21/41346) - ASJ: 0.02880% (1/3472) - OTH: 0.09625% (2/2078)
BP7
The c.648C>T (p.Pro216=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -2.75191 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species.
BP4
SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
Not Met criteria codes
BA1
gnomAD (v2): ALL: 0.01383% (39/281942) - NFE: 0.01945% (25/128566) - AFR: 0.03609% (9/24940) - AMR: 0.01129% (4/35426) - FIN: 0.004022% (1/24862) gnomAD (v3): ALL: 0.02040% (31/151992) - NFE: 0.01029% (7/68012) - AFR: 0.05079% (21/41346) - ASJ: 0.02880% (1/3472) - OTH: 0.09625% (2/2078)
BS4
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS3
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS2
Not applicable
BP5
Not applicable
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
Not applicable
BP1
Not applicable
PS4
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS2
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP4
Not applicable
PP1
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP3
SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PP2
Not applicable
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
Not applicable
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
PM6
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PM2
gnomAD (v2): ALL: 0.01383% (39/281942) - NFE: 0.01945% (25/128566) - AFR: 0.03609% (9/24940) - AMR: 0.01129% (4/35426) - FIN: 0.004022% (1/24862) gnomAD (v3): ALL: 0.02040% (31/151992) - NFE: 0.01029% (7/68012) - AFR: 0.05079% (21/41346) - ASJ: 0.02880% (1/3472) - OTH: 0.09625% (2/2078)
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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