chr8-11757066-A-G

Variant names:

• chr8-11757066-A-G
• rs3729856
• NM_001308093.3:c.1132A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001308093.3(GATA4):​c.1132A>G​(p.Ser378Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,614,072 control chromosomes in the GnomAD database, including 11,064 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.089 (848 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10216 hom.)
• Consequence: GATA4 NM_001308093.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:11
• Conservation: PhyloP100: 0.363
• Publications: 53 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017141104).
• BP6: Variant 8-11757066-A-G is Benign according to our data. Variant chr8-11757066-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44334.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

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.1132A>G	p.Ser378Gly	missense	Exon 6 of 7	NP_001295022.1	P43694-2
	GATA4	NM_002052.5		c.1129A>G	p.Ser377Gly	missense	Exon 6 of 7	NP_002043.2
	GATA4	NM_001308094.2		c.511A>G	p.Ser171Gly	missense	Exon 6 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.1132A>G	p.Ser378Gly	missense	Exon 6 of 7	ENSP00000435712.1	P43694-2
	GATA4	ENST00000886854.1		c.1150A>G	p.Ser384Gly	missense	Exon 6 of 7	ENSP00000556913.1
	GATA4	ENST00000886846.1		c.1132A>G	p.Ser378Gly	missense	Exon 7 of 8	ENSP00000556905.1

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 13494 AN: 152210 Hom.: 848 Cov.: 33

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.0530

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0488

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.0893

GnomAD2 exomes AF: 0.0952 AC: 23909 AN: 251156 AF XY: 0.0966

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.0421

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.112 AC: 163346 AN: 1461744 Hom.: 10216 Cov.: 33 AF XY: 0.112 AC XY: 81236 AN XY: 727164

African (AFR) AF: 0.0198 AC: 662 AN: 33474

American (AMR) AF: 0.0459 AC: 2052 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4621 AN: 26134

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0564 AC: 4865 AN: 86254

European-Finnish (FIN) AF: 0.145 AC: 7762 AN: 53374

Middle Eastern (MID) AF: 0.138 AC: 793 AN: 5764

European-Non Finnish (NFE) AF: 0.122 AC: 136088 AN: 1111944

Other (OTH) AF: 0.108 AC: 6494 AN: 60384

GnomAD4 genome AF: 0.0885 AC: 13487 AN: 152328 Hom.: 848 Cov.: 33 AF XY: 0.0868 AC XY: 6465 AN XY: 74476

African (AFR) AF: 0.0210 AC: 874 AN: 41576

American (AMR) AF: 0.0528 AC: 808 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 639 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5186

South Asian (SAS) AF: 0.0487 AC: 235 AN: 4828

European-Finnish (FIN) AF: 0.140 AC: 1490 AN: 10608

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9131 AN: 68030

Other (OTH) AF: 0.0874 AC: 185 AN: 2116

Alfa AF: 0.116 Hom.: 4719

Bravo AF: 0.0783

TwinsUK AF: 0.116 AC: 429

ALSPAC AF: 0.111 AC: 427

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.140 AC: 1204

ExAC AF: 0.0959 AC: 11648

Asia WGS AF: 0.0270 AC: 98 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.125

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
1	-	3	not provided (4)
-	-	1	Atrioventricular septal defect 4 (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Neonatal insulin-dependent diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	1.5
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.52	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.36
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.29
Sift	Benign	0.42	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.081
MPC		0.16
ClinPred		0.0016	T
GERP RS		0.91
Varity_R		0.044
gMVP		0.40
Mutation Taster		=94/6	polymorphism (auto)

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: rs3729856; hg19: chr8-11614575; COSMIC: COSV58732556; COSMIC: COSV58732556;