chr8-11748855-G-C

Position:

• chr8-11748855-G-C

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.617-61G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,577,196 control chromosomes in the GnomAD database, including 17,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1226 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15779 hom.)
• Consequence: GATA4 NM_001308093.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: -0.0950

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=-0.89).
• BP6: Variant 8-11748855-G-C is Benign according to our data. Variant chr8-11748855-G-C is described in ClinVar as [Benign]. Clinvar id is 433017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748855-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA4	NM_001308093.3	c.617-61G>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.617-61G>C		intron_variant		1	NM_001308093.3	ENSP00000435712.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15992 AN: 152184 Hom.: 1226 Cov.: 33

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0636

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0580

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.140 AC: 199535 AN: 1424894 Hom.: 15779 AF XY: 0.139 AC XY: 99011 AN XY: 711346

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.0529

Gnomad4 ASJ exome AF: 0.179

Gnomad4 EAS exome AF: 0.000278

Gnomad4 SAS exome AF: 0.0653

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.158

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome AF: 0.105 AC: 15983 AN: 152302 Hom.: 1226 Cov.: 33 AF XY: 0.101 AC XY: 7552 AN XY: 74472

Gnomad4 AFR AF: 0.0267

Gnomad4 AMR AF: 0.0634

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0579

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.103

Alfa AF: 0.0910 Hom.: 155

Bravo AF: 0.0940

Asia WGS AF: 0.0300 AC: 107 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-	- -

Congenital heart disease Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	clinical testing	Central Research Laboratory, Sri Devaraj Urs Academy of Higher Education and Research	Jan 07, 2017	- -
Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_008177.2(NM_002052.4):c.617-64G>C in the gene GATA4 has an allele frequency of 0.188 in European (non-Finnish) subpopulation in the gnomAD database. 337 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.33

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: rs10503425; hg19: chr8-11606364; COSMIC: COSV58733836;