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.741C>T (p.Pro247=)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16616523

415835 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2f04ea68-4598-4d14-a8ac-578110f008a4

Approved on: 2022-07-07

Published on: 2022-07-07

HGVS expressions

NM_001754.5:c.741C>T

NM_001754.5(RUNX1):c.741C>T (p.Pro247=)

NC_000021.9:g.34834474G>A

CM000683.2:g.34834474G>A

NC_000021.8:g.36206771G>A

CM000683.1:g.36206771G>A

NC_000021.7:g.35128641G>A

NG_011402.2:g.1155238C>T

ENST00000675419.1:c.741C>T

ENST00000300305.7:c.741C>T

ENST00000344691.8:c.660C>T

ENST00000358356.9:c.660C>T

ENST00000399237.6:c.705C>T

ENST00000399240.5:c.532+25000C>T

ENST00000437180.5:c.741C>T

ENST00000469087.1:n.277C>T

ENST00000482318.5:c.*331C>T

NM_001001890.2:c.660C>T

NM_001122607.1:c.660C>T

NM_001754.4:c.741C>T

NM_001001890.3:c.660C>T

NM_001122607.2:c.660C>T

Likely Benign

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

BP7 BP4 PM2_Supporting

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

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.741C>T (p.Pro247=) is a synonymous variant. As such, a REVEL score is not calculable, and there is no predicted effect on protein function. SpliceAI predicted the following: Acceptor loss 0, Donor loss 0, Acceptor gain 0, Donor gain 0. As such, there is no in silico evidence of an effect on splicing(BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.06724 < 2.0)(BP7). This variant is completely absent from all 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.

BP7

This variant is a SYNONYMOUS variant, which does not result in a protein codon change. As such, a REVEL score is not calculable, and there is no predicted effect on protein function. SpliceAI predicted the following: Acceptor loss 0, Donor loss 0, Acceptor gain 0, Donor gain 0. As such, there is no in silico evidence of an effect on splicing. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.06724 < 2.0) Therefore, BP7 IS MET.

BP4

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1. PM2_SUPPORTING IS MET.

PVS1

This is a synonymous variant, and not a null variant. Therefore, PVS1 is NOT MET.

BA1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1. BA1 is NOT MET.

BS2

This rule is not applicable for MM-VCEP

BS4

An extensive literature search, including PubMed, Google Scholar, Mastermind and other databases reveal no published literature on this variant. Therefore, no segregation data are available. BS4 is NOT MET.

BS3

An extensive literature search, including PubMed, Google Scholar, Mastermind and other databases reveal no published literature on this variant. Therefore, BS3 is NOT MET.

BS1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1. BS1 is NOT MET.

BP5

This rule is not applicable for MM-VCEP

BP2

An extensive literature search, including PubMed, Google Scholar, Mastermind and other databases reveal no published literature on this variant. Therefore, no inheritance data are available. BP2 is NOT MET.

BP3

This rule is not applicable for MM-VCEP

BP1

This rule is not applicable for MM-VCEP

PS1

This is a synonymous variant, and no other pathogenic variants have been identified at aa position 247. Therefore, PS1 is NOT MET.

PS2

An extensive literature search, including PubMed, Google Scholar, Mastermind and other databases reveal no published literature on this variant. Therefore, no data about de novo occurrences are available. BS4 is NOT MET.

PS4

An extensive literature search, including PubMed, Google Scholar, Mastermind and other databases reveal no published literature on this variant. Therefore, no case-control studies are available. PS4 is NOT MET.

PS3

An extensive literature search, including PubMed, Google Scholar, Mastermind and other databases reveal no published literature on this variant. Therefore, PS3 is NOT MET.

PP1

PP4

This rule is not applicable for MM-VCEP

PP3

PP2

This rule is not applicable for MM-VCEP

PM6

PM5

This is a synonymous variant, and no other pathogenic variants have been identified at aa position 247. Therefore, PM5 is NOT MET.

PM1

This synonymous variant occurs outside of the conserved runt homology domain (aa 89-204); therefore, PM1 is NOT MET.

PM3

This rule is not applicable for MM-VCEP

PM4

This is a synonymous variant that does not result in protein length changes. As such, PM4 is NOT MET.

Curation History

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