dbSNP rs55980825: GATA4:p.Cys275Cys (chr8-11750149-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_001308093.3(GATA4):c.825C>T(p.Cys275Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,614,006 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0041 ( 11 hom. )

Consequence

GATA4
NM_001308093.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:11

Conservation

PhyloP100: 1.83

Publications

8 publications found

Variant links:

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

GATA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 8-11750149-C-T is Benign according to our data. Variant chr8-11750149-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44336.

BP7

Synonymous conserved (PhyloP=1.83 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00268 (408/152382) while in subpopulation NFE AF = 0.00492 (335/68044). AF 95% confidence interval is 0.00449. There are 3 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 408 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GATA4	NM_001308093.3	MANE Select	c.825C>T	p.Cys275Cys	synonymous	Exon 4 of 7	NP_001295022.1	P43694-2
GATA4	NM_002052.5		c.822C>T	p.Cys274Cys	synonymous	Exon 4 of 7	NP_002043.2
GATA4	NM_001308094.2		c.204C>T	p.Cys68Cys	synonymous	Exon 4 of 7	NP_001295023.1	B3KUF4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GATA4	ENST00000532059.6	TSL:1 MANE Select	c.825C>T	p.Cys275Cys	synonymous	Exon 4 of 7	ENSP00000435712.1	P43694-2
GATA4	ENST00000886854.1		c.843C>T	p.Cys281Cys	synonymous	Exon 4 of 7	ENSP00000556913.1
GATA4	ENST00000886846.1		c.825C>T	p.Cys275Cys	synonymous	Exon 5 of 8	ENSP00000556905.1

Frequencies

GnomAD3 genomes

AF:

0.00268

AC:

408

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00492

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00221

AC:

556

AN:

251098

AF XY:

0.00219

show subpopulations

Gnomad AFR exome

AF:

0.000986

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000700

Gnomad NFE exome

AF:

0.00337

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00411

AC:

6003

AN:

1461624

Hom.:

Cov.:

AF XY:

0.00398

AC XY:

2893

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33480

American (AMR)

AF:

0.00262

AC:

117

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00111

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000790

AC:

AN:

53160

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00493

AC:

5478

AN:

1112008

Other (OTH)

AF:

0.00404

AC:

244

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

368

735

1103

1470

1838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00268

AC:

408

AN:

152382

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41592

American (AMR)

AF:

0.00131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00492

AC:

335

AN:

68044

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00364

Hom.:

Bravo

AF:

0.00270

EpiCase

AF:

0.00316

EpiControl

AF:

0.00344

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Atrioventricular septal defect 4 (2)

not specified (2)

Atrial septal defect 2 (1)

Cardiovascular phenotype (1)

Primary dilated cardiomyopathy (1)

Tetralogy of Fallot (1)

Ventricular septal defect 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

1.8

Mutation Taster

=91/9

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over