rs772532276

chr8-11708660-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001308093.3(GATA4):c.348C>T(p.Ser116=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000636 in 1,302,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: GATA4 NM_001308093.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.111

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 8-11708660-C-T is Benign according to our data. Variant chr8-11708660-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11708660-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.111 with no splicing effect.
• BS2: High AC in GnomAd at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3	c.348C>T	p.Ser116=	synonymous_variant	2/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6	c.348C>T	p.Ser116=	synonymous_variant	2/7	1	NM_001308093.3	A1

Frequencies

GnomAD3 genomes AF: 0.000429 AC: 65 AN: 151490 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000482

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000827

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00108 AC: 25 AN: 23052 Hom.: 0 AF XY: 0.000770 AC XY: 11 AN XY: 14280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000548

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000358

Gnomad FIN exome AF: 0.000534

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000664 AC: 764 AN: 1151178 Hom.: 0 Cov.: 31 AF XY: 0.000623 AC XY: 346 AN XY: 555592

Gnomad4 AFR exome AF: 0.000214

Gnomad4 AMR exome AF: 0.000233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000108

Gnomad4 FIN exome AF: 0.000433

Gnomad4 NFE exome AF: 0.000755

Gnomad4 OTH exome AF: 0.000345

GnomAD4 genome AF: 0.000429 AC: 65 AN: 151490 Hom.: 0 Cov.: 32 AF XY: 0.000392 AC XY: 29 AN XY: 73988

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000482

Gnomad4 NFE AF: 0.000827

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000635 Hom.: 0

Bravo AF: 0.000646

ClinVar

Significance: Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2021	This variant is associated with the following publications: (PMID: 27374936, 20874241) -
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	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	GATA4: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 11, 2015

- -

Atrioventricular septal defect 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

- -

GATA4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2017

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	-0.52
Cadd	Benign	9.5
Dann	Benign	0.95

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: rs772532276; hg19: chr8-11566169;