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.143G>A (p.Ser48Asn)

CA10014586

2418762 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 95189139-dbbb-426a-980c-f0999bfb4d43
Approved on: 2023-11-13
Published on: 2023-11-13

HGVS expressions

NM_001754.5:c.143G>A
NM_001754.5(RUNX1):c.143G>A (p.Ser48Asn)
NC_000021.9:g.34887051C>T
CM000683.2:g.34887051C>T
NC_000021.8:g.36259348C>T
CM000683.1:g.36259348C>T
NC_000021.7:g.35181218C>T
NG_011402.2:g.1102661G>A
ENST00000675419.1:c.143G>A
ENST00000300305.7:c.143G>A
ENST00000344691.8:c.62G>A
ENST00000358356.9:c.62G>A
ENST00000399237.6:c.107G>A
ENST00000399240.5:c.62G>A
ENST00000437180.5:c.143G>A
ENST00000455571.5:c.104G>A
ENST00000475045.6:c.143G>A
ENST00000482318.5:c.59-6338G>A
NM_001001890.2:c.62G>A
NM_001122607.1:c.62G>A
NM_001754.4:c.143G>A
NM_001001890.3:c.62G>A
NM_001122607.2:c.62G>A

Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 22
PM6 PM2 PM5 PM1 PM3 PM4 BA1 BS2 BS3 BS1 PS3 PS1 PS4 PS2 PVS1 BP7 BP5 BP2 BP1 BP3 PP3 PP2

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
The c.143G>A (NM_001754.5) variant in RUNX1 is a missense variant predicted to cause substitution of serine by asparagine at amino acid 48 (p.S48N). The highest population minor allele frequency in gnomAD v2 is 0.000009310 (1/107408 alleles) in the non-Finnish European population. The variant of unclear origin has only been reported in an 80yo male with CCUS at a VAF=29.63% (Ferrone, 2022, Postdoctoral Thesis). The computational predictor REVEL gives a score of 0.409, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4.
Met criteria codes
BP4
REVEL score = 0.409, which is less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
Not Met criteria codes
PM6
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PM2
- gnomAD (v2): ALL: 0.0004307% (1/232174) - NFE: 0.0009310% (1/107408) - gnomAD (v3): Completely absent with a mean coverage of at least 20X
PM5
S48/S21 variants are reported in Mastermind, but not at a high enough frequency that they would be likely classified as LP/P.
PM1
Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.
PM3
Not applicable
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
- gnomAD (v2): ALL: 0.0004307% (1/232174) - NFE: 0.0009310% (1/107408) - gnomAD (v3): Completely absent with a mean coverage of at least 20X
BS2
Not applicable
BS3
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS1
- gnomAD (v2): ALL: 0.0004307% (1/232174) - NFE: 0.0009310% (1/107408) - gnomAD (v3): Completely absent with a mean coverage of at least 20X
PS3
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS4
The variant was detected at a VAF=29.63% in an 80yo male with initially suspected MDS that was revised to a diagnosis of CCUS, but germline origin isn't clear (Ferrone, 2022, Postdoctoral Thesis). (The variant is not referenced in PMID: 28812720 and PMID: 29463756.)
PS2
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
Not applicable
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
Not applicable
BP3
Not applicable
PP3
REVEL score = 0.409, which is not higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PP2
Not applicable
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