rs804280

Positions:

• chr8-11755189-C-A
• chr8-11755189-C-G
• chr8-11755189-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001308093.3(GATA4):​c.1000+56C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,409,926 control chromosomes in the GnomAD database, including 277,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30361 hom., cov: 32)
  • Exomes 𝑓: 0.62 (247456 hom.)
• Consequence: GATA4 NM_001308093.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:8
• Conservation: PhyloP100: -0.173

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 (BayesDel_noAF=-0.84).
• BP6: Variant 8-11755189-C-A is Benign according to our data. Variant chr8-11755189-C-A is described in ClinVar as [Benign]. Clinvar id is 139596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11755189-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3	c.1000+56C>A		intron_variant		ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6	c.1000+56C>A		intron_variant		1	NM_001308093.3	A1

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94843 AN: 151966 Hom.: 30339 Cov.: 32

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.712

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.825

Gnomad FIN AF: 0.718

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.611

GnomAD4 exome AF: 0.618 AC: 777664 AN: 1257842 Hom.: 247456 AF XY: 0.622 AC XY: 394900 AN XY: 634466

Gnomad4 AFR exome AF: 0.581

Gnomad4 AMR exome AF: 0.789

Gnomad4 ASJ exome AF: 0.437

Gnomad4 EAS exome AF: 0.975

Gnomad4 SAS exome AF: 0.805

Gnomad4 FIN exome AF: 0.695

Gnomad4 NFE exome AF: 0.582

Gnomad4 OTH exome AF: 0.613

GnomAD4 genome AF: 0.624 AC: 94911 AN: 152084 Hom.: 30361 Cov.: 32 AF XY: 0.638 AC XY: 47412 AN XY: 74356

Gnomad4 AFR AF: 0.587

Gnomad4 AMR AF: 0.713

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.980

Gnomad4 SAS AF: 0.823

Gnomad4 FIN AF: 0.718

Gnomad4 NFE AF: 0.581

Gnomad4 OTH AF: 0.615

Alfa AF: 0.590 Hom.: 34998

Bravo AF: 0.623

Asia WGS AF: 0.888 AC: 3086 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	literature only	Molecular Genetics and Enzymology, National Research Centre	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	This variant is associated with the following publications: (PMID: 25928801) -

Congenital heart disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Central Research Laboratory, Sri Devaraj Urs Academy of Higher Education and Research

Jan 07, 2017

- -

Atrioventricular septal defect 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

GATA4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2021

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.56
DANN	Benign	0.55

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: rs804280; hg19: chr8-11612698;