rs55980825

chr8-11750149-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001308093.3(GATA4):c.825C>T(p.Cys275=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,614,006 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0041 (11 hom.)
• Consequence: GATA4 NM_001308093.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:11
• Conservation: PhyloP100: 1.83

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 8-11750149-C-T is Benign according to our data. Variant chr8-11750149-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44336.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=5}. Variant chr8-11750149-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00268 (408/152382) while in subpopulation NFE AF= 0.00492 (335/68044). AF 95% confidence interval is 0.00449. There are 3 homozygotes in gnomad4. There are 174 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 408 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3	c.825C>T	p.Cys275=	synonymous_variant	4/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6	c.825C>T	p.Cys275=	synonymous_variant	4/7	1	NM_001308093.3	A1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152264 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00221 AC: 556 AN: 251098 Hom.: 0 AF XY: 0.00219 AC XY: 298 AN XY: 135794

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.000700

Gnomad NFE exome AF: 0.00337

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00411 AC: 6003 AN: 1461624 Hom.: 11 Cov.: 32 AF XY: 0.00398 AC XY: 2893 AN XY: 727140

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.000790

Gnomad4 NFE exome AF: 0.00493

Gnomad4 OTH exome AF: 0.00404

GnomAD4 genome AF: 0.00268 AC: 408 AN: 152382 Hom.: 3 Cov.: 34 AF XY: 0.00234 AC XY: 174 AN XY: 74518

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00492

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00364 Hom.: 0

Bravo AF: 0.00270

EpiCase AF: 0.00316

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	This variant is associated with the following publications: (PMID: 30590232, 30229885, 28381408, 20874241, 24033266, 27374936, 18076106, 18055909, 12939651) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GATA4: BP4, BS2 -

Atrioventricular septal defect 4 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 07, 2016	p.Cys274Cys in exon 4 of GATA4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.3% (202/66414) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs55980825). -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 04, 2016	- -

Atrial septal defect 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Tetralogy of Fallot Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Ventricular septal defect 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2016

This alteration is classified as likely 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
BayesDel_noAF	Benign	-0.34
Cadd	Benign	12
Dann	Benign	0.77

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

Other links and lift over

dbSNP: rs55980825; hg19: chr8-11607658;