NM_001308093.3:c.487C>T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001308093.3(GATA4):c.487C>T(p.Pro163Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000474 in 1,476,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

GATA4
NM_001308093.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4B:1

Conservation

PhyloP100: 2.46

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 Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000724 (11/151948) while in subpopulation EAS AF= 0.00155 (8/5164). AF 95% confidence interval is 0.00077. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA4	NM_001308093.3 link	c.487C>T	p.Pro163Ser	missense_variant	Exon 2 of 7	ENST00000532059.6	NP_001295022.1	P43694-2B3KUF4B6DU75

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6 link	c.487C>T	p.Pro163Ser	missense_variant	Exon 2 of 7	1	NM_001308093.3	ENSP00000435712.1		P43694-2

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151840

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:

0.00174

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000729

AC:

AN:

82342

Hom.:

AF XY:

0.0000641

AC XY:

AN XY:

46796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000667

Gnomad SAS exome

AF:

0.000121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000333

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1324970

Hom.:

Cov.:

AF XY:

0.0000352

AC XY:

AN XY:

653204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000437

Gnomad4 SAS exome

AF:

0.0000411

Gnomad4 FIN exome

AF:

0.0000608

Gnomad4 NFE exome

AF:

0.0000313

Gnomad4 OTH exome

AF:

0.000146

GnomAD4 genome

AF:

0.0000724

AC:

AN:

151948

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000487

AC:

Asia WGS

AF:

0.00146

AC:

AN:

3440

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tetralogy of Fallot

Pathogenic:2

Dec 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Atrioventricular septal defect 4

Pathogenic:1Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 163 of the GATA4 protein (p.Pro163Ser). This variant is present in population databases (rs387906769, gnomAD 0.05%). This missense change has been observed in individual(s) with congenital heart defects (PMID: 17643447, 18672102, 20874241, 23626780, 27139165, 28161810, 31513339). ClinVar contains an entry for this variant (Variation ID: 30099). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GATA4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Uncertain:1Benign:1

Sep 11, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with congenital heart defects (Rajagopal et al., 2007; Zhang et al., 2008; Peng et al., 2010; Wang et al., 2013; Wang et al., 2016; Liu et al., 2017); Did not segregate with disease in one family in which all affected family members harbored a variant in the ACTC1 gene (Wang et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21110066, 23626780, 17643447, 18672102, 27139165, 28161810, 31513339) -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GATA4: PP2, PP3, PS3:Supporting, BS2 -

Male infertility with azoospermia or oligozoospermia due to single gene mutation

Pathogenic:1

Sep 01, 2023

Laan Lab, Human Genetics Research Group, University of Tartu

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Ventricular septal defect 1

Pathogenic:1

Dec 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Testicular anomalies with or without congenital heart disease

Uncertain:1

Oct 15, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS- 3B Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance. For 46,XY disorders of sex development, incomplete penetrance was suggested in PMID:29670578. For cardiac conditions, a large 3 generation family showed high but incomplete penetrance and variable expressivity (PMID:20347099). (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (gnomAD (v2.1.1): 0.00006185 (7 Het, 0 Hom). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD: p.(Pro163Arg): 0.00000883 (1 Het, 0 Hom). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif. Located in the GATA-N domain (GATA-type transcription activator, N-terminal) (DECIPHER, NCBI Conserved domains, RCSB-PDB). (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity: p.(Pro163Arg): 1 submission in ClinVar as VUS (Atrioventricular septal defect). (N) 0808 - Previous reports of pathogenicity are conflicting. All publications for this variant relate to cardiac conditions. ClinVar: Conflicting interpretations of pathogenicity: 5 submissions: 4x Pathogenic + 1x VUS, the most recent being VUS. LOVD3: VUS and Likely benign. PMID: 28471988: Meta-studies indicate that this variant is not associated with disease (congenital heart disease). PMID: 23626780: this variant appeared in many controls (cardiac study). (N) 0905 - No segregation evidence has been identified for this variant, in association with a disorder of sex development (DSD). (N) 1002 - Moderate functional evidence supporting abnormal protein function. This variant was shown to have impaired binding with ZFMP2 (PMID: 31513339). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Tetralogy of Fallot;C1842778:Atrial septal defect 2;C3280777:Ventricular septal defect 1;C3280781:Atrioventricular septal defect 4

Uncertain:1

Nov 19, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GATA4 c.487C>T (p.Pro163Ser) variant has been reported in at least 10 individuals with predominantly East Asian ancestry affected with congenital heart defects (CHD), including echocardial cushion defect, tetralogy of Fallot, ventricular septal defect, single atrium with single ventricle, pulmonary stenosis, and transposition of the great arteries (Liu Y et al., PMID: 28161810; Peng T et al., PMID: 21110066; Rajagopal SK et al., PMID: 17643447, Shichiri Y et al., PMID: 35751412; Wang E et al., PMID: 23626780; Wang Y et al., PMID: 27139165; Zhang W et al., PMID: 18672102; Zhao Z et al., PMID: 31513339). A meta-analysis study showed that this is no significant association between the c.487C>T variant and CHD risk (OR 1.16, 95% CI: 0.48-2.78) (Zhang Y et al., PMID: 28471988). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.06% in the East Asian population. This variant resides within the transcriptional activation domain of GATA4 that is defined as a critical functional domain (Morrisey EE et al., PMID: 9079680; Pikkarainen S et al., PMID: 15249177). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GATA4 function. Another variant in the same codon, c.488C>G (p.Pro163Arg), has been reported in an affected individual with a VSD but was inherited from an unaffected father and not present in an affected sibling (Butler TL et al., PMID: 20874241, ClinVar Variation ID: 639476). This variant has been reported in the ClinVar database as a germline variant with conflicting classifications, including pathogenic by one submitter, uncertain significance by three submitters, and likely benign by one submitter. Due to conflicting information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;.;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.89

M_CAP

Pathogenic

0.99

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.3

L;L;.

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-0.83

N;N;.

REVEL

Pathogenic

0.69

Sift

Benign

0.32

T;T;.

Sift4G

Benign

0.24

T;T;T

Polyphen

0.67

P;.;.

Vest4

0.47

MutPred

0.79

Gain of phosphorylation at P163 (P = 0.0582);Gain of phosphorylation at P163 (P = 0.0582);.;

MVP

0.92

MPC

2.2

ClinPred

0.38

GERP RS

3.7

Varity_R

0.10

gMVP

0.71

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