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.984A>G (p.Thr328=)

CA10014227

258187 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3b529aa5-afa3-4671-bdf2-1cbfaf0aa32f

Approved on: 2022-07-07

Published on: 2022-07-07

HGVS expressions

NM_001754.4:c.984A>G

NM_001754.4(RUNX1):c.984A>G (p.Thr328=)

NC_000021.9:g.34792594T>C

CM000683.2:g.34792594T>C

NC_000021.8:g.36164891T>C

CM000683.1:g.36164891T>C

NC_000021.7:g.35086761T>C

NG_011402.2:g.1197118A>G

ENST00000675419.1:c.984A>G

ENST00000300305.7:c.984A>G

ENST00000344691.8:c.903A>G

ENST00000399240.5:c.711A>G

ENST00000437180.5:c.984A>G

ENST00000482318.5:c.*574A>G

NM_001001890.2:c.903A>G

NM_001001890.3:c.903A>G

NM_001754.5:c.984A>G

NM_001754.5(RUNX1):c.984A>G (p.Thr328=)

Likely Benign

BP4 BP7

PVS1 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP1 BP5 PS2 PS4 PS3 PS1 PP1 PP4 PP3 PP2 PM6 PM2 PM1 PM5 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_001754.4(RUNX1):c.984A>G (p.Thr328=) is a synonymous variant. There is NO predicted effect on the gene product; REVEL is not calculable. SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00. As such, there appears to be NO effect on splicing (BP4. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -3.2495 which is < 2.0)(BP7). In summary, this variant meets the 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.

BP4

This variant produces a synonymous change in all observed transcripts from an ACA to ACG codon; the consequent amino acid in both cases is Threonine. As such there is NO predicted effect on the gene product; REVEL and SpiceAI scores are not calculable. Given that no effect is computationally predicted for this variant, BP4 IS MET.

BP7

This IS a synonymous variant. For this variant, SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00. As such, there appears to be NO effect on splicing. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -3.2495 which is < 2.0); as such BP7 IS MET (BP7).

PVS1

This is a synonymous variant; as such PSV1 is NOT met.

BA1

MAF of 0.00076 (0.076%, 3/3966, 3969 alleles) in the African subpopulation of the ExAc cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BA1 IS NOT MET). Note: The variant is classified as likely benign based on BS1 alone with no contradictory evidence supporting pathogenicity.

BS2

This rule is not applicable for MM-VCEP

BS4

This variant has been reported in NO probands with relevant phenotypic features. BS4 is NOT met.

BS3

There are NO in vitro or in vivo functional studies performed on this variant. BS3 is NOT MET.

BS1

MAF of 0.00076 (0.076%, 3/3966, 3969 alleles) in the African subpopulation of the ExAc cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1 IS MET). Note: The variant is classified as likely benign based on BS1 alone with no contradictory evidence supporting pathogenicity.

BP2

This synonymous variant has not been observed in a relevant inheritance pattern with a pathogenic variant. BP2 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

PS2

This variant has not been assessed as being de novo or had confirmation of maternity/paternity. PM6 is NOT MET.

PS4

There is no reported case-control studies for this synonymous variant; PS4 is NOT met.

PS3

There are NO in vitro or in vivo functional studies performed on this variant. PS3 is NOT MET.

PS1

This synonymous variant is found at amino acid 328. The only other identified pathogenic variants located at amino acid 328 are RUNX1 p.Y328X and p.T328fs. Both of these are nonsense variants. There are no other missense SNV variants described at the RUNX1 328 aa site. Further, this variant is a synonymous variant. As such, PS1 is NOT met.

PP1

This variant has been reported in NO probands with relevant phenotypic features. PP1 is NOT met.

PP4

This rule is not applicable for MM-VCEP

PP3

This variant produces a synonymous change in all observed transcripts from an ACA to ACG codon; the consequent amino acid in both cases is Threonine. As such there is NO predicted effect on the gene product; PP3 is NOT met. Scores are not calculable by REVEL or SpiceAI.

PP2

This rule is not applicable for MM-VCEP

PM6

This variant has not been assessed as being de novo or had confirmation of maternity/paternity. PM6 is NOT MET.

PM2

MAF of 0.00076 (0.076%, 3/3966, 3969 alleles) in the African subpopulation of the ExAc cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (PM2 IS NOT MET). Note: The variant is classified as likely benign based on BS1 alone with no contradictory evidence supporting pathogenicity.

PM1

This variant is synonymous and falls outside of the conserved Runt-Homology Domain (aa 89-204). As such, PM1 is NOT met.

PM5

PM3

This rule is not applicable for MM-VCEP

PM4

This variant is a SYNONYMOUS variant; PM4 is NOT met.

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