VCV000339794.8 - ClinVar

NM_001754.5(RUNX1):c.*4188G>C

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Likely benign

for Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Classification is based on the expert panel submission

May 2021 by ClinGen Myeloid Malignancy Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001754.5(RUNX1):c.*4188G>C

Variation ID: 339794 Accession: VCV000339794.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.12 21: 34787947 (GRCh38) [ NCBI UCSC ] 21: 36160244 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Jul 18, 2022	May 26, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001754.5:c.*4188G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_001001890.3:c.*4188G>C		3 prime UTR
NC_000021.9:g.34787947C>G
NC_000021.8:g.36160244C>G
NG_011402.2:g.1201765G>C
LRG_482:g.1201765G>C
LRG_482t1:c.*4188G>C

... more HGVS ... less HGVS

Protein change

Other names

NM_001754.4(RUNX1):c.*4188G>C

Canonical SPDI

NC_000021.9:34787946:C:G

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00010

Trans-Omics for Precision Medicine (TOPMed) 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00038

Links

ClinGen: CA10644605 dbSNP: rs761390141 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RUNX1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1582	2011

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	May 28, 2019	RCV000321119.9
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	Likely benign (1)	reviewed by expert panel	May 26, 2021	RCV002264680.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (May 26, 2021) C Contributing to aggregate classification	reviewed by expert panel (ClinGen MyeloMalig ACMG Specifications v2)	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (Autosomal dominant inheritance)	ClinGen Myeloid Malignancy Variant Curation Expert Panel FDA Recognized Database Accession: SCV002546394.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/912add43-9404-4257-a2a6-c545861ad7ef Comment: show This 3' UTR c.*4188G>C variant is located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP = -0.665764 in GRCh38). The variant is present in gnomAD at an allele frequency between 0.015% and 0.15% in a general continental population (European, non-Finnish, subpopulation: 0.03528% in v3) with >5 variant alleles and a minimum of 2000 total alleles (BS1) and has not been described in the literature. 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: BS1. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Likely benign (May 28, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	Mendelics Accession: SCV001141292.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Jan 13, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	Illumina Laboratory Services, Illumina Accession: SCV000435859.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This 3' UTR c.*4188G>C variant is located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP = -0.665764 in GRCh38). The variant is present in gnomAD at an allele frequency between 0.015% and 0.15% in a general continental population (European, non-Finnish, subpopulation: 0.03528% in v3) with >5 variant alleles and a minimum of 2000 total alleles (BS1) and has not been described in the literature. 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: BS1.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/912add43-9404-4257-a2a6-c545861ad7ef	-	-	-	-

Text-mined citations for rs761390141 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 06, 2026