rs878854481

Variant names:

• chr8-11757070-G-A
• rs878854481
• NM_001308093.3:c.1136G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-11757070-G-A
• chr8-11757070-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001308093.3(GATA4):​c.1136G>A​(p.Ser379Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S379I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GATA4 NM_001308093.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.83
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• atrial septal defect 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• structural congenital heart disease, multiple types - GATA4

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• testicular anomalies with or without congenital heart disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• metabolic syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• pancreatic hypoplasia-diabetes-congenital heart disease syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA4	NM_001308093.3	c.1136G>A	p.Ser379Asn	missense_variant	Exon 6 of 7	ENST00000532059.6	NP_001295022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6	c.1136G>A	p.Ser379Asn	missense_variant	Exon 6 of 7	1	NM_001308093.3	ENSP00000435712.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrioventricular septal defect 4 Uncertain:1

Aug 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with GATA4-related conditions. 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. 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 not expected to disrupt GATA4 protein function. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 378 of the GATA4 protein (p.Ser378Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T;T;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0073
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.0	.;.;M;.;.
PhyloP100		4.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.98	N;N;N;N;.
REVEL	Uncertain	0.48
Sift	Benign	0.074	T;T;T;T;.
Sift4G	Benign	0.31	T;T;T;T;T
Polyphen		0.11	.;.;B;.;.
Vest4		0.33
MutPred		0.18		.;.;Loss of glycosylation at S378 (P = 0.0339);.;.;
MVP		0.82
MPC		0.15
ClinPred		0.63	D
GERP RS		5.0
Varity_R		0.097
gMVP		0.48
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs878854481; hg19: chr8-11614579;