Evidence Repository - Clinical Genome Resources

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_001754.5(RUNX1):c.1252A>G (p.Met418Val)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA16616511

409820 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f4a80743-9655-49a4-ae49-617843862694

Approved on: 2024-09-18

Published on: 2024-09-18

HGVS expressions

NM_001754.5:c.1252A>G

NM_001754.5(RUNX1):c.1252A>G (p.Met418Val)

NC_000021.9:g.34792326T>C

CM000683.2:g.34792326T>C

NC_000021.8:g.36164623T>C

CM000683.1:g.36164623T>C

NC_000021.7:g.35086493T>C

NG_011402.2:g.1197386A>G

ENST00000675419.1:c.1252A>G

ENST00000300305.7:c.1252A>G

ENST00000344691.8:c.1171A>G

ENST00000399240.5:c.979A>G

ENST00000437180.5:c.1252A>G

ENST00000482318.5:c.*842A>G

NM_001001890.2:c.1171A>G

NM_001754.4:c.1252A>G

NM_001001890.3:c.1171A>G

Likely Benign

BP4 BS1

BP7 BP5 BP2 BP3 BP1 PS2 PS4 PS3 PS1 PVS1 PP1 PP4 PP3 PP2 PM1 PM5 PM3 PM4 PM6 PM2 BA1 BS2 BS4 BS3

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.1252A>G (p.Met418Val) is a missense variant. It has a MAF of 0.0001747 (0.01747%, 3/17174, 17174 alleles) in the African/African American population of the gnomAD v2.1.1 cohort (21-36164623-T-C (GRCh37)) and MAF of 0.0003559 (0.03559%, 14/39338, 39338 alleles) in the African/African American population of gnomAD v3.1.2 cohort (21-34792326-T-C (GRCh38)) is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense has a REVEL score ≤0.50 (0.140) and SpliceAI score is ≤0.20 (0.00) (BP4). This variant has been reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria, but PS4 can not be applied with BS1 (PS4 not applied). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4.

BP4

This missense has a REVEL score <0.50 (0.140) and SpliceAI score of 0.

BS1

MAF of 0.0001747 (0.01747%, 3/17174, 17174 alleles) in the African/African American population of the gnomAD v2.1.1 cohort (21-36164623-T-C (GRCh37)) and MAF of 0.0003559 (0.03559%, 14/39338, 39338 alleles) in the African/African American population of gnomAD v3.1.2 cohort (21-34792326-T-C (GRCh38)) is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1).

BP7

This is a missense variant.

BP5

This rule is not applicable for MM-VCEP.

BP2

Presence of another pathogenic RUNX1 variant is unknown.

BP3

This rule is not applicable for MM-VCEP.

BP1

This rule is not applicable for MM-VCEP.

PS2

No published de novo cases.

PS4

This variant has been reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria, but PS4 can not be applied with BS1 (PS4 not applied).

PS3

PMID 34166225 was reviewed. Two transactivation assays show this variant has activity 71.33% (transactivation-Luciferase reporter assay with SPI1) and 103.30% (transactivation-GMZA reporter assay). Only a transactivation-Luciferase reporter assay can be applied to MM-VCEP and on this assay, it does not fulfill PS3.

PS1

A variant at the same amino acid residue has not been reported using the MM-VCEP guidelines.

PVS1

This is a missense variant not predicted to affect protein length.

PP1

Segregation information unavailable.

PP4

This rule is not applicable for MM-VCEP.

PP3

Fulfills BP4.

PP2

This rule is not applicable for MM-VCEP.

PM1

The variant p.Met418Val is not within the list of RUNX1 hotspot variants for MM-VCEP.

PM5

A variant at the same amino acid residue has not been reported using the MM-VCEP guidelines.

PM3

This rule is not applicable for MM-VCEP.

PM4

This is a missense variant not predicted to cause protein length change.

PM6

No published de novo cases.

PM2

This variant meets BS1.

BA1

This variant meets BS1.

BS2

This rule is not applicable for MM-VCEP.

BS4

Segregation information unavailable.

BS3

Curation History

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