rs116781972

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001308093.3(GATA4):c.802G>A(p.Val268Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V268L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

GATA4
NM_001308093.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 7.93

Variant links:

Genes affected

GATA4 (HGNC:4173): (GATA binding protein 4) This gene encodes a member of the GATA family of zinc-finger transcription factors. Members of this family recognize the GATA motif which is present in the promoters of many genes. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function, and is necessary for normal testicular development. Mutations in this gene have been associated with cardiac septal defects. Additionally, alterations in gene expression have been associated with several cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

GATA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017153054).

BP6

Variant 8-11750126-G-A is Benign according to our data. Variant chr8-11750126-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3 linkuse as main transcript	c.802G>A	p.Val268Met	missense_variant	4/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6 linkuse as main transcript	c.802G>A	p.Val268Met	missense_variant	4/7	1	NM_001308093.3	A1	P43694-2

Frequencies

GnomAD3 genomes

AF:

0.0000919

AC:

AN:

152280

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:

0.00269

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000271

AC:

AN:

251224

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00370

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:

0.0000349

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00123

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152398

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74526

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000945

ExAC

AF:

0.000305

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2016

The p.V267M variant (also known as c.799G>A), located in coding exon 3 of the GATA4 gene, results from a G to A substitution at nucleotide position 799. The valine at codon 267 is replaced by methionine, an amino acid with highly similar properties. In a study of 384 sporadic Chinese patients with congenital heart disease, this alteration was reported in 2 patients and also in 4 of the 957 controls (Wang E et al. PLoS ONE, 2013 Apr;8:e62138). This variant was previously reported in the SNPDatabase as rs116781972. Based on data from ExAC, the A allele was only reported in East Asian population with a frequency of approximately 0.034% (3/8618). Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.54% (1/184) Southern Han Chinese alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Atrioventricular septal defect 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2020

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T;T;.;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.017

T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.95

.;.;L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.84

N;N;N;N;.

REVEL

Pathogenic

0.69

Sift

Benign

0.14

T;T;T;T;.

Sift4G

Benign

0.19

T;T;D;D;D

Polyphen

0.40

.;.;B;.;.

Vest4

0.68

MVP

0.98

MPC

1.7

ClinPred

0.17

GERP RS

5.4

Varity_R

0.16

gMVP

0.77

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