rs3735819

Positions:

• chr8-11748803-T-C
• chr8-11748803-T-G

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.617-113T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 1,276,656 control chromosomes in the GnomAD database, including 374,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49802 hom., cov: 33)
  • Exomes 𝑓: 0.76 (324915 hom.)
• Consequence: GATA4 NM_001308093.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: 0.332

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=-0.87).
• BP6: Variant 8-11748803-T-C is Benign according to our data. Variant chr8-11748803-T-C is described in ClinVar as [Benign]. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in Lovd as [Benign]. Variant chr8-11748803-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA4	NM_001308093.3	c.617-113T>C		intron_variant		ENST00000532059.6	NP_001295022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6	c.617-113T>C		intron_variant		1	NM_001308093.3	ENSP00000435712	A1

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122250 AN: 152134 Hom.: 49742 Cov.: 33

Gnomad AFR AF: 0.898

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.764

GnomAD4 exome AF: 0.756 AC: 849976 AN: 1124404 Hom.: 324915 AF XY: 0.759 AC XY: 436396 AN XY: 575192

Gnomad4 AFR exome AF: 0.905

Gnomad4 AMR exome AF: 0.859

Gnomad4 ASJ exome AF: 0.643

Gnomad4 EAS exome AF: 0.976

Gnomad4 SAS exome AF: 0.876

Gnomad4 FIN exome AF: 0.833

Gnomad4 NFE exome AF: 0.722

Gnomad4 OTH exome AF: 0.756

GnomAD4 genome AF: 0.804 AC: 122370 AN: 152252 Hom.: 49802 Cov.: 33 AF XY: 0.813 AC XY: 60534 AN XY: 74452

Gnomad4 AFR AF: 0.898

Gnomad4 AMR AF: 0.815

Gnomad4 ASJ AF: 0.635

Gnomad4 EAS AF: 0.984

Gnomad4 SAS AF: 0.887

Gnomad4 FIN AF: 0.849

Gnomad4 NFE AF: 0.728

Gnomad4 OTH AF: 0.766

Alfa AF: 0.752 Hom.: 8823

Bravo AF: 0.804

Asia WGS AF: 0.937 AC: 3258 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.833, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -

Congenital heart disease Pathogenic:1 Benign:1

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_008177.2(NM_002052.4):c.617-116T>C in the gene GATA4 has an allele frequency of 0.898 in African subpopulation in the gnomAD database. 128 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -
Pathogenic, no assertion criteria provided	clinical testing	Central Research Laboratory, Sri Devaraj Urs Academy of Higher Education and Research	Jan 07, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.1
DANN	Benign	0.67

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: rs3735819; hg19: chr8-11606312;