rs114868912

Positions:

chr8-11757075-G-A

Variant summary

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

The NM_001308093.3(GATA4):c.1141G>A(p.Val381Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,614,034 control chromosomes in the GnomAD database, including 88 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 (★★).

Frequency

Genomes: 𝑓 0.011 ( 31 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 57 hom. )

Consequence

GATA4
NM_001308093.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.07

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=0.0032224953).

BP6

Variant 8-11757075-G-A is Benign according to our data. Variant chr8-11757075-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11757075-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1662/152346) while in subpopulation AFR AF= 0.0349 (1453/41574). AF 95% confidence interval is 0.0335. There are 31 homozygotes in gnomad4. There are 849 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1662 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3 linkuse as main transcript	c.1141G>A	p.Val381Met	missense_variant	6/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6 linkuse as main transcript	c.1141G>A	p.Val381Met	missense_variant	6/7	1	NM_001308093.3	A1	P43694-2

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1662

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0351

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00405

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00521

AC:

1308

AN:

251068

Hom.:

AF XY:

0.00551

AC XY:

748

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.0338

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00348

Gnomad SAS exome

AF:

0.0194

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00257

AC:

3750

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

2131

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0389

Gnomad4 AMR exome

AF:

0.00170

Gnomad4 ASJ exome

AF:

0.000957

Gnomad4 EAS exome

AF:

0.00798

Gnomad4 SAS exome

AF:

0.0188

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.00386

GnomAD4 genome

AF:

0.0109

AC:

1662

AN:

152346

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

849

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0349

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00367

Gnomad4 SAS

AF:

0.0188

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.0120

ESP6500AA

AF:

0.0356

AC:

157

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00626

AC:

760

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 20, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GATA4: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2019	This variant is associated with the following publications: (PMID: 31513339, 28511407, 26997702, 30766556, 31115957, 26490186, 19678963, 28843068, 18055909, 17352393, 28372585, 16604480, 20981092, 21631294, 22995991, 22011241, 28161810, 21276881) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 23, 2021	- -

Neonatal insulin-dependent diabetes mellitus

Benign:1

Likely benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Potent mutations in GATA4 gene are associated with neonatal diabetes, decreased insulin production due to pancreatic aplasia or hypoplasia. Also associated with isolated cardiac abnormalities in children, like atrial septal defects. However no sufficient evidence is found to ascertain the role of this particular variant rs114868912 yet. -

Atrioventricular septal defect 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

GATA4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 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

Jun 17, 2016

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

0.059

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.24

T;T;T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.031

MetaRNN

Benign

0.0032

T;T;T;T;T

MetaSVM

Uncertain

-0.037

MutationAssessor

Benign

-0.28

.;.;N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.23

N;N;N;N;.

REVEL

Uncertain

0.35

Sift

Benign

0.37

T;T;T;T;.

Sift4G

Benign

0.53

T;T;T;T;T

Polyphen

0.0030

.;.;B;.;.

Vest4

0.10

MVP

0.59

MPC

0.16

ClinPred

0.010

GERP RS

2.1

Varity_R

0.035

gMVP

0.21

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