rs56166237

chr8-11708411-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001308093.3(GATA4):c.99G>T(p.Ala33=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,538,132 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (22 hom.)
• Consequence: GATA4 NM_001308093.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0400

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006820202).
• BP6: Variant 8-11708411-G-T is Benign according to our data. Variant chr8-11708411-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 220979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00222 (337/152128) while in subpopulation EAS AF= 0.0249 (127/5108). AF 95% confidence interval is 0.0213. There are 1 homozygotes in gnomad4. There are 239 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 337 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3	c.99G>T	p.Ala33=	synonymous_variant	2/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6	c.99G>T	p.Ala33=	synonymous_variant	2/7	1	NM_001308093.3	A1

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 152020 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00361 AC: 487 AN: 135020 Hom.: 8 AF XY: 0.00333 AC XY: 247 AN XY: 74102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000647

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0301

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.00221

GnomAD4 exome AF: 0.00137 AC: 1903 AN: 1386004 Hom.: 22 Cov.: 31 AF XY: 0.00129 AC XY: 886 AN XY: 684450

Gnomad4 AFR exome AF: 0.0000625

Gnomad4 AMR exome AF: 0.000831

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0300

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.00228

GnomAD4 genome AF: 0.00222 AC: 337 AN: 152128 Hom.: 1 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74380

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0249

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000907 Hom.: 0

Bravo AF: 0.00136

ExAC AF: 0.00212 AC: 186

Asia WGS AF: 0.00608 AC: 21 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2021	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Atrioventricular septal defect 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2017

This alteration is classified as 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_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	5.4
Dann	Benign	0.89
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.74	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D;D
Sift4G	Benign	0.093	T
Vest4		0.23
MVP		0.83
ClinPred		0.024	T
GERP RS		1.4

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: rs56166237; hg19: chr8-11565920;