rs779684582

Variant names:

• chr8-11758454-C-A
• rs779684582
• NM_001308093.3:c.1311C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-11758454-C-A
• chr8-11758454-C-G
• chr8-11758454-C-T

Variant summary

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

The NM_001308093.3(GATA4):​c.1311C>A​(p.His437Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H437H) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GATA4 NM_001308093.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.91
• 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308093.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA4	NM_001308093.3	MANE Select	c.1311C>A	p.His437Gln	missense	Exon 7 of 7	NP_001295022.1	P43694-2
	GATA4	NM_002052.5		c.1308C>A	p.His436Gln	missense	Exon 7 of 7	NP_002043.2
	GATA4	NM_001308094.2		c.690C>A	p.His230Gln	missense	Exon 7 of 7	NP_001295023.1	B3KUF4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA4	ENST00000532059.6	TSL:1 MANE Select	c.1311C>A	p.His437Gln	missense	Exon 7 of 7	ENSP00000435712.1	P43694-2
	GATA4	ENST00000886854.1		c.1329C>A	p.His443Gln	missense	Exon 7 of 7	ENSP00000556913.1
	GATA4	ENST00000886846.1		c.1311C>A	p.His437Gln	missense	Exon 8 of 8	ENSP00000556905.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	8.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.30	N
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		-2.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.050	T
Polyphen		0.97	D
Vest4		0.50
MutPred		0.27		Gain of disorder (P = 0.0578)
MVP		0.98
MPC		0.64
ClinPred		0.78	D
GERP RS		-3.9
Varity_R		0.39
gMVP		0.83
Mutation Taster		=83/17	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: rs779684582; hg19: chr8-11615963; COSMIC: COSV105898216; COSMIC: COSV105898216;