rs55633527

chr8-11758378-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/19 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 1.25

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3	c.1235C>T	p.Ala412Val	missense_variant	7/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6	c.1235C>T	p.Ala412Val	missense_variant	7/7	1	NM_001308093.3	A1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152198 Hom.: 3 Cov.: 32

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.: 7 AF XY: 0.00361 AC XY: 491 AN XY: 135916

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.: 20 Cov.: 31 AF XY: 0.00217 AC XY: 1577 AN XY: 727218

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.: 3 Cov.: 32 AF XY: 0.00389 AC XY: 290 AN XY: 74488

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.: 0

Bravo AF: 0.00126

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00360 AC: 437

EpiCase AF: 0.00125

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	GATA4: BS1, BS2 -
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) -

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

Invitae

Jan 24, 2024

- -

GATA4-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

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

- -

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	T
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	D
MetaRNN	Benign	0.0045	T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
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	T
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

Other links and lift over

dbSNP: rs55633527; hg19: chr8-11615887; COSMIC: COSV58732442; COSMIC: COSV58732442;