rs200319078

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001308093.3(GATA4):c.1183C>A(p.Pro395Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,150 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00070 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 27 hom. )

Consequence

GATA4
NM_001308093.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.108

Variant links:

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]

GATA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037125945).

BP6

Variant 8-11758326-C-A is Benign according to our data. Variant chr8-11758326-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 412737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11758326-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000696 (106/152292) while in subpopulation SAS AF= 0.0208 (100/4814). AF 95% confidence interval is 0.0175. There are 5 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA4	NM_001308093.3 linkuse as main transcript	c.1183C>A	p.Pro395Thr	missense_variant	7/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6 linkuse as main transcript	c.1183C>A	p.Pro395Thr	missense_variant	7/7	1	NM_001308093.3	A1	P43694-2

Frequencies

GnomAD3 genomes

AF:

0.000697

AC:

106

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00228

AC:

572

AN:

251284

Hom.:

AF XY:

0.00292

AC XY:

397

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0184

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00107

AC:

1569

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1099

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0169

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00147

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152292

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000117

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00252

AC:

306

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 09, 2017	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	- -

Atrioventricular septal defect 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

46,XY sex reversal 3

Benign:1

Benign, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Aug 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.070

Cadd

Benign

Dann

Benign

0.85

DEOGEN2

Benign

0.27

T;T;.;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.85

MetaRNN

Benign

0.0037

T;T;T;T

MetaSVM

Uncertain

0.41

MutationTaster

Benign

0.91

N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.69

N;N;N;.

REVEL

Uncertain

0.37

Sift

Benign

0.13

T;T;T;.

Sift4G

Benign

0.49

T;T;T;T

Polyphen

0.025

.;B;.;.

Vest4

0.051

MutPred

0.18

.;Gain of catalytic residue at P394 (P = 0.039);.;.;

MVP

0.81

MPC

0.19

ClinPred

0.014

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over