rs55633527

Positions:

chr8-11758378-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001308093.3(GATA4):c.1235C>T(p.Ala412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,614,136 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A412A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 20 hom. )

Consequence

GATA4
NM_001308093.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: 1.25

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044817626).

BP6

Variant 8-11758378-C-T is Benign according to our data. Variant chr8-11758378-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11758378-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00303 (461/152316) while in subpopulation NFE AF= 0.00226 (154/68018). AF 95% confidence interval is 0.00197. There are 3 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA4	NM_001308093.3 linkuse as main transcript	c.1235C>T	p.Ala412Val	missense_variant	7/7	ENST00000532059.6	NP_001295022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6 linkuse as main transcript	c.1235C>T	p.Ala412Val	missense_variant	7/7	1	NM_001308093.3	ENSP00000435712	A1	P43694-2

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

461

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0233

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00358

AC:

900

AN:

251478

Hom.:

AF XY:

0.00361

AC XY:

491

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0247

Gnomad NFE exome

AF:

0.00271

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00224

AC:

3273

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

1577

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0241

Gnomad4 NFE exome

AF:

0.00161

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00303

AC:

461

AN:

152316

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

290

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0233

Gnomad4 NFE

AF:

0.00226

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.00126

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00360

AC:

437

EpiCase

AF:

0.00125

EpiControl

AF:

0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2020	This variant is associated with the following publications: (PMID: 32748548, 18055909, 20874241, 21631294, 20363377, 12939651) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GATA4: BS1, BS2 -

Thoracic aortic aneurysm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Atrioventricular septal defect 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Tetralogy of Fallot;C1842778:Atrial septal defect 2;C3280777:Ventricular septal defect 1;C3280781:Atrioventricular septal defect 4;C3809858:Testicular anomalies with or without congenital heart disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 07, 2022

- -

GATA4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2019

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). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

9.7

DANN

Benign

0.64

DEOGEN2

Benign

0.29

T;T;.;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.71

FATHMM_MKL

Uncertain

0.79

MetaRNN

Benign

0.0045

T;T;T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

1.8

.;L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.51

N;N;N;.

REVEL

Uncertain

0.32

Sift

Benign

0.14

T;T;T;.

Sift4G

Benign

0.55

T;T;T;T

Polyphen

0.012

.;B;.;.

Vest4

0.042

MVP

0.59

MPC

0.16

ClinPred

0.0069

GERP RS

4.8

Varity_R

0.030

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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