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_001754.5(RUNX1):c.1311C>G (p.Thr437=)

CA512341068

463981 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: dc7830e1-364f-445f-a206-d3e8c93a86b5

Approved on: 2022-07-07

Published on: 2022-07-07

HGVS expressions

NM_001754.5:c.1311C>G

NM_001754.5(RUNX1):c.1311C>G (p.Thr437=)

NC_000021.9:g.34792267G>C

CM000683.2:g.34792267G>C

NC_000021.8:g.36164564G>C

CM000683.1:g.36164564G>C

NC_000021.7:g.35086434G>C

NG_011402.2:g.1197445C>G

ENST00000675419.1:c.1311C>G

ENST00000300305.7:c.1311C>G

ENST00000344691.8:c.1230C>G

ENST00000399240.5:c.1038C>G

ENST00000437180.5:c.1311C>G

ENST00000482318.5:c.*901C>G

NM_001001890.2:c.1230C>G

NM_001754.4:c.1311C>G

NM_001001890.3:c.1230C>G

Likely Benign

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

PM2_Supporting BP4 BP7

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

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

NM_001754.5(RUNX1):c.1311C>G (p.Thr437=) is s synonymous variant. Computation evidence is not calculable for the effect of this SYNONYMOUS variant on protein function. The REVEL score is not calculable. Splice AI predicts a 0.00 score for acceptor loss, donor loss, acceptor gain, and donor gain(BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -3.62398 < 2.0)(BP7). This synonymous variant is absent from all examined population databases with at least 20x coverage for RUNX1(PM2_supporting). 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: BP4, BP7, PM2_supporting

PM2_Supporting

This synonymous variant is absent from all examined population databases with at least 20x coverage for RUNX1. Therefore, PM2_SUPPORTING is met.

BP4

Computation evidence is not calculable for the effect of this SYNONYMOUS variant on protein function. The REVEL score is not calculable. Splice AI predicts a 0.00 score for acceptor loss, donor loss, acceptor gain, and donor gain. BP4 IS MET.

BP7

Computation evidence is not calculable for the effect of this SYNONYMOUS variant on protein function. Splice AI predicts a 0.00 score for acceptor loss, donor loss, acceptor gain, and donor gain. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -3.62398 < 2.0). Therefore, BP7 IS MET.

BA1

This synonymous variant is absent from all examined population databases with at least 20x coverage for RUNX1.

PP1

After extensive investigation of multiple literature sources, no published segregation data for this variant could be identified. Therefore, PP1 is NOT MET.

PP4

This rule is not applicable for MM-VCEP

PP3

PP2

This rule is not applicable for MM-VCEP

PM1

This is a synonymous variant at aa 437 that falls outside of the conserved runt homology domain (RHD) (aa 89-204). Therefore, PM1 is NOT MET.

PM5

This is a SYNONYMOUS variant; at aa position, one other variant of unclear significance (p.T437I) has been detected previously. Further, this variant is outside of the conserved runt homology domain (aa 89-204). Therefore, PM5 is NOT MET.

PM3

This rule is not applicable for MM-VCEP

PM4

This is a SYNONYMOUS variant that occurs outside of the conserved runt homology domain. PM4 is NOT met.

PM6

After extensive investigation of multiple literature sources, no data could be identified about de novo occurrence of this variant. Therefore, PM6 is NOT MET.

BS2

This rule is not applicable for MM-VCEP

BS4

After extensive investigation of multiple literature sources, no published segregation data for this variant could be identified. Therefore, BS4 is NOT MET.

BS3

After an extensive search of PubMed, Medline, Mastermind, and other resources, no published functional studies for this variant could be found. Therefore, BS3 is NOT MET.

BS1

This synonymous variant is absent from all examined population databases with at least 20x coverage for RUNX1.

PVS1

This is a SYNONYMOUS variant, and is NOT a null variant. Therefore, PVS1 is NOT met.

PS2

After extensive investigation of multiple literature sources, no data could be identified about de novo occurrence of this variant. Therefore, PS2 is NOT MET.

PS4

After extensive investigation of multiple literature sources, no published case control studies could be identified. Therefore, PS4 is NOT MET.

PS3

After an extensive search of PubMed, Medline, Mastermind, and other resources, no published functional studies for this variant could be found. Therefore, PS3 is NOT MET.

PS1

BP2

After extensive investigation of multiple literature sources, no data could be identified about inheritance pattern in cis with a pathogenic variant for this RUNX1 variant. Therefore, PM6 is NOT MET.

BP3

This rule is not applicable for MM-VCEP

BP1

This rule is not applicable for MM-VCEP

BP5

This rule is not applicable for MM-VCEP

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