rs762292084

Positions:

chr21-34792388-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: This c.1190A>G (p.Gln397Arg) missense variant has a MAF of 0.003624 (0.3624%, 53/14624, 202938 alleles) in the East Asian subpopulation of the gnomAD v2 cohort, which is ≥ 0.0015 (0.15%) (BA1). The high allele frequency accounts for reports of this variant in affected individuals: 2 heterozygous patients with AML (PMID:19808697), a homozygous patient with personal and family history of thrombocytopenia (PMID:30103613), and other reports of this variant in patients with MDS, AML, and T-ALL that have not been confirmed to be of germline origin (PMID:17910630, 24523240, 24792891, 24850867, 28157215, 29279377). Furthermore, an abstract indicated that a dual luciferase assay used to assess this variant's transactivation ability in K562 cells was normal, although this data was not published in a peer-reviewed format (Huang et al., 2009, ASH Abstract 3468 - https://ashpublications.org/blood/article/114/22/3468/132805/High-Frequency-of-C-Terminal-Frame-Shift-Mutations). This missense variant have a REVEL score <0.5 (0.238), and is not predicted by SpliceAI, MES, or SSF-like to have a splicing impact (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014193/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:3

Conservation

PhyloP100: 5.59

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

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.1190A>G	p.Gln397Arg	missense_variant	9/9	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.1190A>G	p.Gln397Arg	missense_variant	9/9		NM_001754.5	ENSP00000501943	A1	Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0000793

AC:

AN:

151324

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00219

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000268

AC:

AN:

171874

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

91722

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00352

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000481

AC:

AN:

1414298

Hom.:

Cov.:

AF XY:

0.0000429

AC XY:

AN XY:

699014

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00163

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000276

Gnomad4 OTH exome

AF:

0.0000683

GnomAD4 genome

AF:

0.0000792

AC:

AN:

151448

Hom.:

Cov.:

AF XY:

0.0000810

AC XY:

AN XY:

74042

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00219

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000103

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the germline of an individual with pediatric ALL (Cecile Liu et al., 2022); This variant is associated with the following publications: (PMID: 24523240, Liu2022, 19808697, Huang_2009_Abstract) -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jul 07, 2022

This c.1190A>G (p.Gln397Arg) missense variant has a MAF of 0.003624 (0.3624%, 53/14624, 202938 alleles) in the East Asian subpopulation of the gnomAD v2 cohort, which is ≥ 0.0015 (0.15%) (BA1). The high allele frequency accounts for reports of this variant in affected individuals: 2 heterozygous patients with AML (PMID: 19808697), a homozygous patient with personal and family history of thrombocytopenia (PMID: 30103613), and other reports of this variant in patients with MDS, AML, and T-ALL that have not been confirmed to be of germline origin (PMID: 17910630, 24523240, 24792891, 24850867, 28157215, 29279377). Furthermore, an abstract indicated that a dual luciferase assay used to assess this variant's transactivation ability in K562 cells was normal, although this data was not published in a peer-reviewed format (Huang et al., 2009, ASH Abstract 3468 - https://ashpublications.org/blood/article/114/22/3468/132805/High-Frequency-of-C-Terminal-Frame-Shift-Mutations). This missense variant have a REVEL score <0.5 (0.238), and is not predicted by SpliceAI, MES, or SSF-like to have a splicing impact (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;.;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.0

M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.9

D;D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Benign

0.37

T;T;T;T

Polyphen

0.98

D;P;P;.

Vest4

0.57

MutPred

0.65

Gain of methylation at Q370 (P = 0.0245);.;.;.;

MVP

0.57

MPC

1.1

ClinPred

0.20

GERP RS

5.1

Varity_R

0.52

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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