chr8-11757012-G-T

Variant names:

• chr8-11757012-G-T
• rs368489876
• NM_001308093.3:c.1078G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001308093.3(GATA4):​c.1078G>T​(p.Glu360*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GATA4 NM_001308093.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.06
• Publications: 9 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-11757012-G-T is Pathogenic according to our data. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-11757012-G-T is described in CliVar as Pathogenic. Clinvar id is 967905.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA4	NM_001308093.3	c.1078G>T	p.Glu360*	stop_gained	Exon 6 of 7	ENST00000532059.6	NP_001295022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6	c.1078G>T	p.Glu360*	stop_gained	Exon 6 of 7	1	NM_001308093.3	ENSP00000435712.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrioventricular septal defect 4 Pathogenic:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu359*) in the GATA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GATA4 are known to be pathogenic (PMID: 12845333, 15235040). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with GATA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 967905). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		6.1
Vest4		0.96
GERP RS		5.8
Mutation Taster		=2/198	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: rs368489876; hg19: chr8-11614521;