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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001754.4(RUNX1):c.402T>C (p.Ala134=)

CA512318752

463995 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ae9643a6-e40d-4165-a575-d96063f3599c

HGVS expressions

NM_001754.4:c.402T>C

NM_001754.4(RUNX1):c.402T>C (p.Ala134=)

NC_000021.9:g.34880663A>G

CM000683.2:g.34880663A>G

NC_000021.8:g.36252960A>G

CM000683.1:g.36252960A>G

NC_000021.7:g.35174830A>G

NG_011402.2:g.1109049T>C

ENST00000675419.1:c.402T>C

ENST00000300305.7:c.402T>C

ENST00000344691.8:c.321T>C

ENST00000358356.9:c.321T>C

ENST00000399237.6:c.366T>C

ENST00000399240.5:c.321T>C

ENST00000437180.5:c.402T>C

ENST00000455571.5:c.363T>C

ENST00000482318.5:c.109T>C

NM_001001890.2:c.321T>C

NM_001122607.1:c.321T>C

NM_001001890.3:c.321T>C

NM_001122607.2:c.321T>C

NM_001754.5:c.402T>C

NM_001754.5(RUNX1):c.402T>C (p.Ala134=)

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

BP4 BP7 PM2_Supporting

PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP1 BP5 PS3 PS2 PS4 PS1 BA1 PP1 PP4 PP3 PP2 PM3 PM1 PM5 PM4 PM6

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

This c.402T>C (p.Ala134=) synonymous variant is located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP score = -2.40196 in GRCh38); it is not predicted to have any splicing impact per SpliceAI (BP7+BP4). The variant is absent from population databases, including gnomAD v2 and v3 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1 (version 2): BP4, BP7, and PM2_supporting.

BP4

SpliceAI does not show any significant splicing impact (Δ scores ≤ 0.20).

BP7

Synonymous variant located at a non-conserved nucleotide (PhyloP = -2.40196 in GRCh38), and the variant is the reference nucleotide in one primate and/or 3 mammals. SpliceAI does not show a splicing impact.

PM2_Supporting

gnomAD v2: absent with ≥20x coverage gnomAD v3: absent with ≥20x coverage

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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

BS1

gnomAD v2: absent with ≥20x coverage gnomAD v3: absent with ≥20x coverage

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

BP5

Not applicable

PS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

Literature was not found in HGMD, Google/Google Scholar searches, or COSMIC.

PS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BA1

gnomAD v2: absent with ≥20x coverage gnomAD v3: absent with ≥20x coverage

PP1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

Not applicable

PP3

SpliceAI does not show any significant splicing impact (Δ scores ≤ 0.20).

PP2

Not applicable

PM3

Not applicable

PM1

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

PM4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2022-07-07

Published on: 2022-07-07

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