NM_001308093.3:c.1125C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001308093.3(GATA4):​c.1125C>T​(p.Tyr375Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,172 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000095 ( 1 hom. )

Consequence

GATA4
NM_001308093.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.08

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
BP6
Variant 8-11757059-C-T is Benign according to our data. Variant chr8-11757059-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 412740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-2.08 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000951 (139/1461804) while in subpopulation MID AF = 0.000694 (4/5766). AF 95% confidence interval is 0.000236. There are 1 homozygotes in GnomAdExome4. There are 70 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GATA4NM_001308093.3 linkc.1125C>T p.Tyr375Tyr synonymous_variant Exon 6 of 7 ENST00000532059.6 NP_001295022.1 P43694-2B3KUF4B6DU75

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GATA4ENST00000532059.6 linkc.1125C>T p.Tyr375Tyr synonymous_variant Exon 6 of 7 1 NM_001308093.3 ENSP00000435712.1 P43694-2

Frequencies

GnomAD3 genomes
AF:
0.0000985
AC:
15
AN:
152250
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.000955
GnomAD2 exomes
AF:
0.000131
AC:
33
AN:
251320
AF XY:
0.000118
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000167
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000951
AC:
139
AN:
1461804
Hom.:
1
Cov.:
32
AF XY:
0.0000963
AC XY:
70
AN XY:
727208
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.000224
AC:
10
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.000383
AC:
10
AN:
26136
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39700
South Asian (SAS)
AF:
0.000104
AC:
9
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53384
Middle Eastern (MID)
AF:
0.000694
AC:
4
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000827
AC:
92
AN:
1111980
Other (OTH)
AF:
0.000199
AC:
12
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
10
20
29
39
49
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000984
AC:
15
AN:
152368
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74508
show subpopulations
African (AFR)
AF:
0.0000481
AC:
2
AN:
41586
American (AMR)
AF:
0.000131
AC:
2
AN:
15312
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000132
AC:
9
AN:
68036
Other (OTH)
AF:
0.000945
AC:
2
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000197
Hom.:
0
Bravo
AF:
0.0000869
EpiCase
AF:
0.000436
EpiControl
AF:
0.000237

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Atrioventricular septal defect 4 Benign:1
Jan 26, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Sep 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

GATA4: BP4, BP7 -

Cardiovascular phenotype Benign:1
Jun 13, 2024
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.66
CADD
Benign
0.045
DANN
Benign
0.89
PhyloP100
-2.1
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs56330552; hg19: chr8-11614568; API