rs115372595

chr8-11756974-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001308093.3(GATA4):c.1040C>T(p.Ala347Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,614,262 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (2 hom.)
• Consequence: GATA4 NM_001308093.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 3.07

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 (MetaRNN=0.018835962).
• BP6: Variant 8-11756974-C-T is Benign according to our data. Variant chr8-11756974-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 30100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11756974-C-T is described in UniProt as null. Variant chr8-11756974-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00143 (218/152378) while in subpopulation NFE AF= 0.00245 (167/68036). AF 95% confidence interval is 0.00215. There are 0 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 218 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3	c.1040C>T	p.Ala347Val	missense_variant	6/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6	c.1040C>T	p.Ala347Val	missense_variant	6/7	1	NM_001308093.3	A1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00155 AC: 391 AN: 251448 Hom.: 0 AF XY: 0.00161 AC XY: 219 AN XY: 135910

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00240 AC: 3505 AN: 1461884 Hom.: 2 Cov.: 32 AF XY: 0.00231 AC XY: 1679 AN XY: 727246

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00289

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152378 Hom.: 0 Cov.: 33 AF XY: 0.00125 AC XY: 93 AN XY: 74514

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00245

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00199 Hom.: 0

Bravo AF: 0.00134

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00178 AC: 216

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrioventricular septal defect 4 Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2007	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 16, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 18, 2020

This variant is associated with the following publications: (PMID: 31962012, 20592452, 22011241, 25093829, 26997702, 29368431, 26014430, 27899157, 17643447, 20981092) -

GATA4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

46,XY sex reversal 3 Benign:1

Benign, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Aug 26, 2019

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

This alteration is classified as likely 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
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.69	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.019	T;T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;N;N;N;.
REVEL	Uncertain	0.59
Sift	Benign	0.13	T;T;T;T;.
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.11	.;.;B;.;.
Vest4		0.33
MVP		0.99
MPC		0.20
ClinPred		0.011	T
GERP RS		3.9
Varity_R		0.058
gMVP		0.62

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: rs115372595; hg19: chr8-11614483;