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.351+2T>A

CA410203328

943551 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f21ff2a6-f832-499b-baf6-64d8bb779c47

Approved on: 2022-03-24

Published on: 2022-07-05

HGVS expressions

NM_001754.5:c.351+2T>A

NM_001754.5(RUNX1):c.351+2T>A

NC_000021.9:g.34886841A>T

CM000683.2:g.34886841A>T

NC_000021.8:g.36259138A>T

CM000683.1:g.36259138A>T

NC_000021.7:g.35181008A>T

NG_011402.2:g.1102871T>A

ENST00000675419.1:c.351+2T>A

ENST00000300305.7:c.351+2T>A

ENST00000344691.8:c.270+2T>A

ENST00000358356.9:c.270+2T>A

ENST00000399237.6:c.315+2T>A

ENST00000399240.5:c.270+2T>A

ENST00000437180.5:c.351+2T>A

ENST00000455571.5:c.312+2T>A

ENST00000482318.5:c.59-6128T>A

NM_001001890.2:c.270+2T>A

NM_001122607.1:c.270+2T>A

NM_001754.4:c.351+2T>A

NM_001001890.3:c.270+2T>A

NM_001122607.2:c.270+2T>A

Likely Pathogenic

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

PM2_Supporting PVS1

BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP7 BP5 PS4 PS2 PS3 PS1 BA1 PP1 PP4 PP3 PP2 PM6 PM1 PM5 PM3 PM4

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The c.351+2T>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and is expected to result in nonsense-mediated mRNA decay (PVS1). 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 pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1 and PM2_supporting

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

PVS1

The c.351+2T>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and is expected to result in nonsense-mediated mRNA decay (PVS1)

BS2

This rule is not applicable for MM-VCEP

BS4

No case studies found

BS3

No functional studies found for exact variant

BS1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

BP2

No homozygotes present within gnomAD v2.1.1 and v3.1.2.

BP3

This rule is not applicable for MM-VCEP

BP4

Cannot be applied with PVS1 (SpliceAI Donor loss 1.00 ≥0.38)

BP1

This rule is not applicable for MM-VCEP

BP7

PhyloP score 5.54 >2.0 therefore area is conserved and does not meet BP7

BP5

This rule is not applicable for MM-VCEP

PS4

No case studies found with exact variant

PS2

No case studies found

PS3

No functional studies found for exact variant

PS1

The c.351 variant is the same amino acid change as a previously established pathogenic variant (ClinVar ID 561236) curated using MM-VCEP rules for RUNX1 but only applied to missense variants

BA1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

PP1

No case studies found

PP4

This rule is not applicable for MM-VCEP

PP3

Cannot be applied with PVS1 (SpliceAI Donor loss 1.00 ≥0.38)

PP2

This rule is not applicable for MM-VCEP

PM6

No case studies found

PM1

Not a missense variant

PM5

Not a missense variant

PM3

This rule is not applicable for MM-VCEP

PM4

Not an inframe deletion/insertion

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