rs1282433424

Positions:

• chr8-11755094-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The ENST00000532059.6(GATA4):​c.961C>T​(p.Arg321Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R321Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GATA4 ENST00000532059.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.73

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-11755095-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1431327.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9
• PP5: Variant 8-11755094-C-T is Pathogenic according to our data. Variant chr8-11755094-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 545667.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr8-11755094-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA4	NM_001308093.3	c.961C>T	p.Arg321Trp	missense_variant	5/7	ENST00000532059.6	NP_001295022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6	c.961C>T	p.Arg321Trp	missense_variant	5/7	1	NM_001308093.3	ENSP00000435712	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Atrial septal defect 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Cardiovascular Institute

Oct 01, 2017

- -

Atrioventricular septal defect 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 320 of the GATA4 protein (p.Arg320Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with an atrial septal defect and pancreatic agenesis and ventricular septal defects (PMID: 20854389, 29377543). ClinVar contains an entry for this variant (Variation ID: 545667). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GATA4 protein function. Experimental studies have shown that this missense change affects GATA4 function (PMID: 20854389). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;D;.;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.6	D;D;D;D;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.91
MutPred		0.41		.;.;Gain of methylation at K321 (P = 0.0672);.;.;
MVP		0.98
MPC		0.70
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1282433424; hg19: chr8-11612603;