chr21-34799341-G-A

Position:

chr21-34799341-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP2

This summary comes from the ClinGen Evidence Repository: This synonymous variant is present in gnomAD (v2 and v3) at an allele frequency >0.15% with at least 5 alleles in any general continental population (BA1); in addition, the variant was found in homozygosity in the population database (BP2). Although the variant is predicted by SSF and MES to create a putative cryptic donor splice site at c.925 (insignificant prediction by SpliceAI), evolutionary conservation prediction algorithms predict the site as being weakly conserved (PhyloP score: 1.25 > 0.1 [-14.1;6.4]), and the variant is not the reference nucleotide in one primate and/or three mammal species, SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10%. In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014267/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.010 ( 24 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 9 hom. )

Consequence

RUNX1
NM_001754.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 1.01

Variant links:

Genes affected

RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RUNX1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.927C>T	p.Gly309=	synonymous_variant	8/9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.927C>T	p.Gly309=	synonymous_variant	8/9		NM_001754.5	ENSP00000501943	A1	Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1561

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00282

AC:

709

AN:

251490

Hom.:

AF XY:

0.00205

AC XY:

278

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0384

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.00103

AC:

1499

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000862

AC XY:

627

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0353

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.00281

GnomAD4 genome

AF:

0.0103

AC:

1565

AN:

152326

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

751

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0360

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00624

Hom.:

Bravo

AF:

0.0121

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

RUNX1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jan 12, 2021

This synonymous variant is present in gnomAD (v2 and v3) at an allele frequency >0.15% with at least 5 alleles in any general continental population (BA1); in addition, the variant was found in homozygosity in the population database (BP2). Although the variant is predicted by SSF and MES to create a putative cryptic donor splice site at c.925 (insignificant prediction by SpliceAI), evolutionary conservation prediction algorithms predict the site as being weakly conserved (PhyloP score: 1.25 > 0.1 [-14.1;6.4]), and the variant is not the reference nucleotide in one primate and/or three mammal species, SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10%. In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP2. -

Acute myeloid leukemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over