rs745379

Positions:

• chr8-11758186-A-G

Variant summary

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

The ENST00000532059.6(GATA4):​c.1150-107A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,092,154 control chromosomes in the GnomAD database, including 114,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12854 hom., cov: 32)
  • Exomes 𝑓: 0.45 (101174 hom.)
• Consequence: GATA4 ENST00000532059.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 0.0220

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=-0.94).
• BP6: Variant 8-11758186-A-G is Benign according to our data. Variant chr8-11758186-A-G is described in ClinVar as [Benign]. Clinvar id is 433015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11758186-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA4	NM_001308093.3	c.1150-107A>G		intron_variant		ENST00000532059.6	NP_001295022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6	c.1150-107A>G		intron_variant		1	NM_001308093.3	ENSP00000435712	A1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58856 AN: 151944 Hom.: 12850 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.423

GnomAD4 exome AF: 0.446 AC: 419686 AN: 940092 Hom.: 101174 AF XY: 0.447 AC XY: 218518 AN XY: 489278

Gnomad4 AFR exome AF: 0.258

Gnomad4 AMR exome AF: 0.236

Gnomad4 ASJ exome AF: 0.623

Gnomad4 EAS exome AF: 0.0260

Gnomad4 SAS exome AF: 0.336

Gnomad4 FIN exome AF: 0.369

Gnomad4 NFE exome AF: 0.504

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.387 AC: 58889 AN: 152062 Hom.: 12854 Cov.: 32 AF XY: 0.373 AC XY: 27734 AN XY: 74344

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.639

Gnomad4 EAS AF: 0.0219

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.347

Gnomad4 NFE AF: 0.508

Gnomad4 OTH AF: 0.418

Alfa AF: 0.443 Hom.: 1781

Bravo AF: 0.377

Asia WGS AF: 0.148 AC: 517 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.229, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -
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, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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.1147-107A>G in the gene GATA4 has an allele frequency of 0.510 in European (non-Finnish) subpopulation in the gnomAD database. 2668 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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.7
DANN	Benign	0.38

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: rs745379; hg19: chr8-11615695; COSMIC: COSV104405995; COSMIC: COSV104405995;