rs115099192

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000532059.6(GATA4):c.1223C>A(p.Pro408Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000381 in 1,614,222 control chromosomes in the GnomAD database, including 1 homozygotes. 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. P408A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

GATA4
ENST00000532059.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:3

Conservation

PhyloP100: 4.87

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011231691).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000276 (42/152348) while in subpopulation EAS AF= 0.00367 (19/5182). AF 95% confidence interval is 0.0024. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA4	NM_001308093.3 linkuse as main transcript	c.1223C>A	p.Pro408Gln	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.1223C>A	p.Pro408Gln	missense_variant	7/7	1	NM_001308093.3	ENSP00000435712	A1	P43694-2

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000513

AC:

129

AN:

251464

Hom.:

AF XY:

0.000493

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00353

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000392

AC:

573

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

293

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000957

Gnomad4 EAS exome

AF:

0.00806

Gnomad4 SAS exome

AF:

0.00140

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000674

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000276

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00367

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000288

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000560

AC:

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tetralogy of Fallot

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2008

- -

Ventricular septal defect 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2010

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 31, 2019

Variant classified as Uncertain Significance - Favor Benign. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 TOF patient (sporadic) (Zhang 2008), in 3 individuals (het) with disorders of sexual develpment (Eggers 2016). Liu 2017 further reported this variant in 4/600 patients with conotruncal heart defects and 1/300 controls. Qian 2017 reported the variant in 2 individuals with TOF and POF (also carried V380M, previously associated with VSD))). Identified in 0.3% of East Asian chromosomes in gnomAD. Present in ClinVar (ID 30103) with conflicting interpretations (B, Uncertain significance). -

Microcephaly

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

- -

Atrial septal defect 2;C3280777:Ventricular septal defect 1;C3280781:Atrioventricular septal defect 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2024

Identified in several individuals with congenital heart defects (PMID: 18672102, 19678963, 21110066, 20654103, 21631294, 26490186, 28161810, 28372585, 30152191, 31115957); Identified in association with early onset diabetes and variations of sex characteristics, including individuals without heart anomalies (PMID: 27899157, 27810688, 29735817); Identified in two siblings with developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome who where compound heterozygous for two NARS2 variants (PMID: 35703918); Functional studies show inconsistent data, including one study that found p.(P407Q) results in ~50% reduction in transactivation compared to wild type protein whereas another study showed protein behavior similar to wild type (PMID: 29735817, 31962012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19678963, 26490186, 24583203, 21110066, 20654103, 20592452, 22648249, 22959235, 26997702, 27899157, 28161810, 28372585, 29735817, 30152191, 31115957, 21631294, 31513339, 31962012, 34426522, 32508047, 27810688, 18672102, 35703918, 38456293, 38375489, 35863714, 38274337, 35047139) -

Testicular anomalies with or without congenital heart disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with GATA4-related cardiac disease. (I) 0107 - This gene is associated with autosomal dominant disease. A number a different cardiac conditions are caused by variants in GATA4, however association with differences of sex development (DSD) is not well-established (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to glutamine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of GATA4-related cardiac disease (gnomAD (v2) 132 heterozygotes, 0 homozygotes). (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (17 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated zinc finger DNA binding domain (NCBI). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Alternative changes at the same residue, to alanine and arginine, have previously been classified as VUS in relation to atrioventricular septal defect (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting for both cardiac and DSD conditions, however more recent reports consistently report the variant as benign in relation to DSD (ClinVar, LOVD, HGMD, OMIM, PMID: 32992319). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Atrioventricular septal defect 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

46,XY sex reversal 3

Benign:1

Benign, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Aug 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.0056

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

T;D;.;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.90

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.7

.;M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.4

N;D;D;.

REVEL

Pathogenic

0.71

Sift

Benign

0.032

D;D;D;.

Sift4G

Benign

0.092

T;T;T;T

Polyphen

0.68

.;P;.;.

Vest4

0.38

MVP

0.94

MPC

0.18

ClinPred

0.090

GERP RS

4.8

Varity_R

0.26

gMVP

0.72

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