rs387906769

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P163R) has been classified as Uncertain significance.

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:3B: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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3 linkuse as main transcript	c.487C>T	p.Pro163Ser	missense_variant	2/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6 linkuse as main transcript	c.487C>T	p.Pro163Ser	missense_variant	2/7	1	NM_001308093.3	A1	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:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tetralogy of Fallot

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2010	- -

Atrioventricular septal defect 4

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 13, 2022	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GATA4 protein function. 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2010	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2019	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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	GATA4: PP2, PP3, PS3:Supporting, BS2 -

Male infertility with azoospermia or oligozoospermia due to single gene mutation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Sep 01, 2023

- -

Ventricular septal defect 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2010

- -

Testicular anomalies with or without congenital heart disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 15, 2020

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 -

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;.

MutationTaster

Benign

1.0

D;D;D

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