8-11708799-C-G

Variant names:

• chr8-11708799-C-G
• rs387906769
• NM_001308093.3:c.487C>G

Variant summary

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

The ENST00000532059.6(GATA4):​c.487C>G​(p.Pro163Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000755 in 1,324,970 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P163S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: GATA4 ENST00000532059.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• 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: ENST00000532059.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA4	NM_001308093.3	MANE Select	c.487C>G	p.Pro163Ala	missense	Exon 2 of 7	NP_001295022.1
	GATA4	NM_002052.5		c.487C>G	p.Pro163Ala	missense	Exon 2 of 7	NP_002043.2
	GATA4	NM_001308094.2		c.-6+8021C>G		intron	N/A	NP_001295023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA4	ENST00000532059.6	TSL:1 MANE Select	c.487C>G	p.Pro163Ala	missense	Exon 2 of 7	ENSP00000435712.1
	GATA4	ENST00000335135.8	TSL:5	c.487C>G	p.Pro163Ala	missense	Exon 2 of 7	ENSP00000334458.4
	GATA4	ENST00000622443.3	TSL:5	c.487C>G	p.Pro163Ala	missense	Exon 3 of 8	ENSP00000482268.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.55e-7 AC: 1 AN: 1324970 Hom.: 0 Cov.: 31 AF XY: 0.00000153 AC XY: 1 AN XY: 653204

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26508

American (AMR) AF: 0.00 AC: 0 AN: 28106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22790

East Asian (EAS) AF: 0.00 AC: 0 AN: 29742

South Asian (SAS) AF: 0.00 AC: 0 AN: 72980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3888

European-Non Finnish (NFE) AF: 9.50e-7 AC: 1 AN: 1053140

Other (OTH) AF: 0.00 AC: 0 AN: 54930

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.5	L
PhyloP100		2.5
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.61
Sift	Benign	0.082	T
Sift4G	Benign	0.097	T
Polyphen		0.45	P
Vest4		0.30
MutPred		0.56		Loss of glycosylation at P163 (P = 0.0321)
MVP		0.83
MPC		1.4
ClinPred		0.60	D
GERP RS		3.7
Varity_R		0.10
gMVP		0.65
Mutation Taster		=70/30	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: rs387906769; hg19: chr8-11566308;