rs980402710

Variant names:

• chr8-11708575-G-T
• rs980402710
• NM_001308093.3:c.263G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001308093.3(GATA4):​c.263G>T​(p.Gly88Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,370,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G88G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: GATA4 NM_001308093.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.0580
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34009713).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

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.263G>T	p.Gly88Val	missense	Exon 2 of 7	NP_001295022.1	P43694-2
	GATA4	NM_002052.5		c.263G>T	p.Gly88Val	missense	Exon 2 of 7	NP_002043.2
	GATA4	NM_001308094.2		c.-6+7797G>T		intron	N/A	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.263G>T	p.Gly88Val	missense	Exon 2 of 7	ENSP00000435712.1	P43694-2
	GATA4	ENST00000886854.1		c.263G>T	p.Gly88Val	missense	Exon 2 of 7	ENSP00000556913.1
	GATA4	ENST00000886846.1		c.263G>T	p.Gly88Val	missense	Exon 3 of 8	ENSP00000556905.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151996 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

GnomAD2 exomes AF: 0.000156 AC: 4 AN: 25666 AF XY: 0.0000629

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000140 AC: 17 AN: 1218356 Hom.: 0 Cov.: 31 AF XY: 0.0000101 AC XY: 6 AN XY: 592940

African (AFR) AF: 0.00 AC: 0 AN: 24242

American (AMR) AF: 0.00 AC: 0 AN: 13474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18092

East Asian (EAS) AF: 0.00 AC: 0 AN: 27262

South Asian (SAS) AF: 0.00 AC: 0 AN: 51780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3490

European-Non Finnish (NFE) AF: 0.0000160 AC: 16 AN: 999698

Other (OTH) AF: 0.0000200 AC: 1 AN: 49966

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Atrioventricular septal defect 4 (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Tetralogy of Fallot;C1842778:Atrial septal defect 2;C3280777:Ventricular septal defect 1;C3280781:Atrioventricular septal defect 4;C3809858:Testicular anomalies with or without congenital heart disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.36	N
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.1	L
PhyloP100		0.058
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.61	N
REVEL	Uncertain	0.42
Sift	Benign	0.15	T
Sift4G	Benign	0.24	T
Polyphen		0.0060	B
Vest4		0.18
MutPred		0.46		Loss of glycosylation at P87 (P = 0.1109)
MVP		0.86
MPC		0.013
ClinPred		0.012	T
GERP RS		1.3
Varity_R		0.11
gMVP		0.65
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: rs980402710; hg19: chr8-11566084; COSMIC: COSV106465191;