rs115372595

Variant names:

• chr8-11756974-C-T
• rs115372595
• NM_001308093.3:c.1040C>T

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.1040C>T​(p.Ala347Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,614,262 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A347S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (2 hom.)
• Consequence: GATA4 NM_001308093.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: 3.07
• Publications: 19 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=0.018835962).
• BP6: Variant 8-11756974-C-T is Benign according to our data. Variant chr8-11756974-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 30100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00143 (218/152378) while in subpopulation NFE AF = 0.00245 (167/68036). AF 95% confidence interval is 0.00215. There are 0 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 218 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.1040C>T	p.Ala347Val	missense	Exon 6 of 7	NP_001295022.1	P43694-2
	GATA4	NM_002052.5		c.1037C>T	p.Ala346Val	missense	Exon 6 of 7	NP_002043.2
	GATA4	NM_001308094.2		c.419C>T	p.Ala140Val	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.1040C>T	p.Ala347Val	missense	Exon 6 of 7	ENSP00000435712.1	P43694-2
	GATA4	ENST00000886854.1		c.1058C>T	p.Ala353Val	missense	Exon 6 of 7	ENSP00000556913.1
	GATA4	ENST00000886846.1		c.1040C>T	p.Ala347Val	missense	Exon 7 of 8	ENSP00000556905.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00155 AC: 391 AN: 251448 AF XY: 0.00161

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00240 AC: 3505 AN: 1461884 Hom.: 2 Cov.: 32 AF XY: 0.00231 AC XY: 1679 AN XY: 727246

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00128 AC: 110 AN: 86258

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00289 AC: 3217 AN: 1112012

Other (OTH) AF: 0.00199 AC: 120 AN: 60396

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152378 Hom.: 0 Cov.: 33 AF XY: 0.00125 AC XY: 93 AN XY: 74514

African (AFR) AF: 0.000625 AC: 26 AN: 41602

American (AMR) AF: 0.000849 AC: 13 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00245 AC: 167 AN: 68036

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00186 Hom.: 0

Bravo AF: 0.00134

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00178 AC: 216

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	1	Atrioventricular septal defect 4 (2)
-	-	2	not provided (2)
-	-	1	46,XY sex reversal 3 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	GATA4-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.69	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.5	L
PhyloP100		3.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.59
Sift	Benign	0.13	T
Sift4G	Benign	0.32	T
Polyphen		0.11	B
Vest4		0.33
MVP		0.99
MPC		0.20
ClinPred		0.011	T
GERP RS		3.9
Varity_R		0.058
gMVP		0.62
Mutation Taster		=36/64	disease causing

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: rs115372595; hg19: chr8-11614483;