8-11748803-T-C

Variant names:

• chr8-11748803-T-C
• rs3735819
• NM_001308093.3:c.617-113T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001308093.3(GATA4):​c.617-113T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 1,276,656 control chromosomes in the GnomAD database, including 374,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49802 hom., cov: 33)
  • Exomes 𝑓: 0.76 (324915 hom.)
• Consequence: GATA4 NM_001308093.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 0.332
• Publications: 5 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 (BayesDel_noAF=-0.87).
• BP6: Variant 8-11748803-T-C is Benign according to our data. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11748803-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA4	NM_001308093.3	c.617-113T>C		intron_variant	Intron 2 of 6	ENST00000532059.6	NP_001295022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6	c.617-113T>C		intron_variant	Intron 2 of 6	1	NM_001308093.3	ENSP00000435712.1

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122250 AN: 152134 Hom.: 49742 Cov.: 33

Gnomad AFR AF: 0.898

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.764

GnomAD4 exome AF: 0.756 AC: 849976 AN: 1124404 Hom.: 324915 AF XY: 0.759 AC XY: 436396 AN XY: 575192

African (AFR) AF: 0.905 AC: 24116 AN: 26660

American (AMR) AF: 0.859 AC: 37938 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 15425 AN: 23976

East Asian (EAS) AF: 0.976 AC: 37233 AN: 38138

South Asian (SAS) AF: 0.876 AC: 69109 AN: 78860

European-Finnish (FIN) AF: 0.833 AC: 42549 AN: 51052

Middle Eastern (MID) AF: 0.743 AC: 3516 AN: 4730

European-Non Finnish (NFE) AF: 0.722 AC: 582875 AN: 807632

Other (OTH) AF: 0.756 AC: 37215 AN: 49212

GnomAD4 genome AF: 0.804 AC: 122370 AN: 152252 Hom.: 49802 Cov.: 33 AF XY: 0.813 AC XY: 60534 AN XY: 74452

African (AFR) AF: 0.898 AC: 37302 AN: 41542

American (AMR) AF: 0.815 AC: 12478 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.635 AC: 2205 AN: 3470

East Asian (EAS) AF: 0.984 AC: 5101 AN: 5186

South Asian (SAS) AF: 0.887 AC: 4281 AN: 4826

European-Finnish (FIN) AF: 0.849 AC: 9021 AN: 10620

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.728 AC: 49522 AN: 67986

Other (OTH) AF: 0.766 AC: 1620 AN: 2114

Alfa AF: 0.764 Hom.: 68156

Bravo AF: 0.804

Asia WGS AF: 0.937 AC: 3258 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 28, 2020

H3Africa Consortium

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.833, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital heart disease Pathogenic:1 Benign:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

NG_008177.2(NM_002052.4):c.617-116T>C in the gene GATA4 has an allele frequency of 0.898 in African subpopulation in the gnomAD database. 128 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -

Jan 07, 2017

Central Research Laboratory, Sri Devaraj Urs Academy of Higher Education and Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Structural congenital heart disease, multiple types - GATA4 Benign:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.1
DANN	Benign	0.67
PhyloP100		0.33
Mutation Taster		=100/0	disease causing (ClinVar)

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: rs3735819; hg19: chr8-11606312;