rs114868912

Variant names:

• chr8-11757075-G-A
• rs114868912
• NM_001308093.3:c.1141G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001308093.3(GATA4):​c.1141G>A​(p.Val381Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,614,034 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (57 hom.)
• Consequence: GATA4 NM_001308093.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.07
• Publications: 23 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032224953).
• BP6: Variant 8-11757075-G-A is Benign according to our data. Variant chr8-11757075-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1662/152346) while in subpopulation AFR AF = 0.0349 (1453/41574). AF 95% confidence interval is 0.0335. There are 31 homozygotes in GnomAd4. There are 849 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1662 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.1141G>A	p.Val381Met	missense	Exon 6 of 7	NP_001295022.1
	GATA4	NM_002052.5		c.1138G>A	p.Val380Met	missense	Exon 6 of 7	NP_002043.2
	GATA4	NM_001308094.2		c.520G>A	p.Val174Met	missense	Exon 6 of 7	NP_001295023.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA4	ENST00000532059.6	TSL:1 MANE Select	c.1141G>A	p.Val381Met	missense	Exon 6 of 7	ENSP00000435712.1
	GATA4	ENST00000886854.1		c.1159G>A	p.Val387Met	missense	Exon 6 of 7	ENSP00000556913.1
	GATA4	ENST00000886846.1		c.1141G>A	p.Val381Met	missense	Exon 7 of 8	ENSP00000556905.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1662 AN: 152228 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00521 AC: 1308 AN: 251068 AF XY: 0.00551

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00257 AC: 3750 AN: 1461688 Hom.: 57 Cov.: 33 AF XY: 0.00293 AC XY: 2131 AN XY: 727136

African (AFR) AF: 0.0389 AC: 1302 AN: 33474

American (AMR) AF: 0.00170 AC: 76 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26134

East Asian (EAS) AF: 0.00798 AC: 317 AN: 39700

South Asian (SAS) AF: 0.0188 AC: 1624 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5758

European-Non Finnish (NFE) AF: 0.000143 AC: 159 AN: 1111902

Other (OTH) AF: 0.00386 AC: 233 AN: 60376

GnomAD4 genome AF: 0.0109 AC: 1662 AN: 152346 Hom.: 31 Cov.: 33 AF XY: 0.0114 AC XY: 849 AN XY: 74498

African (AFR) AF: 0.0349 AC: 1453 AN: 41574

American (AMR) AF: 0.00405 AC: 62 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5182

South Asian (SAS) AF: 0.0188 AC: 91 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68032

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00444 Hom.: 16

Bravo AF: 0.0120

ESP6500AA AF: 0.0356 AC: 157

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00626 AC: 760

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Atrioventricular septal defect 4 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	GATA4-related disorder (1)
-	-	1	Neonatal insulin-dependent diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.031	N
MetaRNN	Benign	0.0032	T
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Benign	-0.28	N
PhyloP100		1.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.23	N
REVEL	Uncertain	0.35
Sift	Benign	0.37	T
Sift4G	Benign	0.53	T
Polyphen		0.0030	B
Vest4		0.10
MVP		0.59
MPC		0.16
ClinPred		0.010	T
GERP RS		2.1
Varity_R		0.035
gMVP		0.21
Mutation Taster		=96/4	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: rs114868912; hg19: chr8-11614584; COSMIC: COSV58734960; COSMIC: COSV58734960;