rs115099192

Variant names:

• chr8-11758366-C-A
• rs115099192
• NM_001308093.3:c.1223C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-11758366-C-A
• chr8-11758366-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001308093.3(GATA4):​c.1223C>A​(p.Pro408Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000381 in 1,614,222 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P408A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: GATA4 NM_001308093.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:3
• Conservation: PhyloP100: 4.87
• Publications: 39 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=0.011231691).
• BP6: Variant 8-11758366-C-A is Benign according to our data. Variant chr8-11758366-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 30103.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000276 (42/152348) while in subpopulation EAS AF = 0.00367 (19/5182). AF 95% confidence interval is 0.0024. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 42 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.1223C>A	p.Pro408Gln	missense	Exon 7 of 7	NP_001295022.1
	GATA4	NM_002052.5		c.1220C>A	p.Pro407Gln	missense	Exon 7 of 7	NP_002043.2
	GATA4	NM_001308094.2		c.602C>A	p.Pro201Gln	missense	Exon 7 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.1223C>A	p.Pro408Gln	missense	Exon 7 of 7	ENSP00000435712.1
	GATA4	ENST00000886854.1		c.1241C>A	p.Pro414Gln	missense	Exon 7 of 7	ENSP00000556913.1
	GATA4	ENST00000886846.1		c.1223C>A	p.Pro408Gln	missense	Exon 8 of 8	ENSP00000556905.1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000513 AC: 129 AN: 251464 AF XY: 0.000493

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00353

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000392 AC: 573 AN: 1461874 Hom.: 1 Cov.: 31 AF XY: 0.000403 AC XY: 293 AN XY: 727234

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26136

East Asian (EAS) AF: 0.00806 AC: 320 AN: 39700

South Asian (SAS) AF: 0.00140 AC: 121 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000674 AC: 75 AN: 1111998

Other (OTH) AF: 0.000497 AC: 30 AN: 60394

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74500

African (AFR) AF: 0.000120 AC: 5 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

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

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000328 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000560 AC: 68

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	46,XY sex reversal 3 (1)
-	1	-	Atrial septal defect 2;C3280777:Ventricular septal defect 1;C3280781:Atrioventricular septal defect 4 (1)
-	-	1	Atrioventricular septal defect 4 (1)
-	1	-	Microcephaly (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	-	1	Testicular anomalies with or without congenital heart disease (1)
1	-	-	Tetralogy of Fallot (1)
1	-	-	Ventricular septal defect 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0056	T
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.011	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.71
Sift	Benign	0.032	D
Sift4G	Benign	0.092	T
Polyphen		0.68	P
Vest4		0.38
MVP		0.94
MPC		0.18
ClinPred		0.090	T
GERP RS		4.8
Varity_R		0.26
gMVP		0.72
Mutation Taster		=2/98	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: rs115099192; hg19: chr8-11615875;