Genetic Variant GATA4:p.Phe154Phe (chr8-11708774-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001308093.3(GATA4):c.462C>T(p.Phe154Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,435,180 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 11 hom. )

Consequence

GATA4
NM_001308093.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.56

Publications

2 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 8-11708774-C-T is Benign according to our data. Variant chr8-11708774-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 412733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.56 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0022 (334/151646) while in subpopulation NFE AF = 0.00365 (247/67738). AF 95% confidence interval is 0.00327. There are 0 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 334 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.462C>T	p.Phe154Phe	synonymous	Exon 2 of 7	NP_001295022.1	P43694-2
GATA4	NM_002052.5		c.462C>T	p.Phe154Phe	synonymous	Exon 2 of 7	NP_002043.2
GATA4	NM_001308094.2		c.-6+7996C>T		intron	N/A	NP_001295023.1	B3KUF4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GATA4	ENST00000532059.6	TSL:1 MANE Select	c.462C>T	p.Phe154Phe	synonymous	Exon 2 of 7	ENSP00000435712.1	P43694-2
GATA4	ENST00000886854.1		c.462C>T	p.Phe154Phe	synonymous	Exon 2 of 7	ENSP00000556913.1
GATA4	ENST00000886846.1		c.462C>T	p.Phe154Phe	synonymous	Exon 3 of 8	ENSP00000556905.1

Frequencies

GnomAD3 genomes

AF:

0.00220

AC:

334

AN:

151538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000723

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00307

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00365

Gnomad OTH

AF:

0.00241

GnomAD2 exomes

AF:

0.00142

AC:

AN:

58518

AF XY:

0.00156

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000423

Gnomad ASJ exome

AF:

0.000209

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00233

Gnomad NFE exome

AF:

0.00297

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00381

AC:

4887

AN:

1283534

Hom.:

Cov.:

AF XY:

0.00366

AC XY:

2311

AN XY:

631258

show subpopulations

African (AFR)

AF:

0.000468

AC:

AN:

25662

American (AMR)

AF:

0.000403

AC:

AN:

22348

Ashkenazi Jewish (ASJ)

AF:

0.000476

AC:

AN:

21024

East Asian (EAS)

AF:

0.00

AC:

AN:

27622

South Asian (SAS)

AF:

0.0000451

AC:

AN:

66482

European-Finnish (FIN)

AF:

0.00260

AC:

AN:

31902

Middle Eastern (MID)

AF:

0.000799

AC:

AN:

3754

European-Non Finnish (NFE)

AF:

0.00445

AC:

4591

AN:

1031822

Other (OTH)

AF:

0.00333

AC:

176

AN:

52918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

272

543

815

1086

1358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<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:

0.00220

AC:

334

AN:

151646

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

159

AN XY:

74130

show subpopulations

African (AFR)

AF:

0.000940

AC:

AN:

41500

American (AMR)

AF:

0.000722

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00307

AC:

AN:

10420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00365

AC:

247

AN:

67738

Other (OTH)

AF:

0.00238

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00275

Hom.:

Bravo

AF:

0.00213

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Atrioventricular septal defect 4 (1)

Cardiovascular phenotype (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

1.6

Mutation Taster

=100/0

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