8-11758829-A-C

Variant names:

• chr8-11758829-A-C
• rs867858
• NM_001308093.3:c.*354A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001308093.3(GATA4):​c.*354A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 352,036 control chromosomes in the GnomAD database, including 19,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.30 (7205 hom., cov: 32)
  • Exomes 𝑓: 0.34 (11943 hom.)
• Consequence: GATA4 NM_001308093.3 3_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.602
• Publications: 28 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA4	NM_001308093.3	MANE Select	c.*354A>C		3_prime_UTR	Exon 7 of 7	NP_001295022.1
	GATA4	NM_002052.5		c.*354A>C		3_prime_UTR	Exon 7 of 7	NP_002043.2
	GATA4	NM_001308094.2		c.*354A>C		3_prime_UTR	Exon 7 of 7	NP_001295023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA4	ENST00000532059.6	TSL:1 MANE Select	c.*354A>C		3_prime_UTR	Exon 7 of 7	ENSP00000435712.1
	GATA4	ENST00000335135.8	TSL:5	c.*354A>C		3_prime_UTR	Exon 7 of 7	ENSP00000334458.4
	GATA4	ENST00000622443.3	TSL:5	c.*354A>C		3_prime_UTR	Exon 8 of 8	ENSP00000482268.2

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45519 AN: 151798 Hom.: 7204 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.321

GnomAD4 exome AF: 0.337 AC: 67505 AN: 200120 Hom.: 11943 Cov.: 0 AF XY: 0.345 AC XY: 37101 AN XY: 107552

African (AFR) AF: 0.241 AC: 1437 AN: 5964

American (AMR) AF: 0.318 AC: 3224 AN: 10152

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1692 AN: 5136

East Asian (EAS) AF: 0.543 AC: 4788 AN: 8814

South Asian (SAS) AF: 0.386 AC: 13766 AN: 35644

European-Finnish (FIN) AF: 0.316 AC: 2885 AN: 9128

Middle Eastern (MID) AF: 0.360 AC: 257 AN: 714

European-Non Finnish (NFE) AF: 0.316 AC: 36072 AN: 114310

Other (OTH) AF: 0.330 AC: 3384 AN: 10258

GnomAD4 genome AF: 0.300 AC: 45528 AN: 151916 Hom.: 7205 Cov.: 32 AF XY: 0.305 AC XY: 22641 AN XY: 74260

African (AFR) AF: 0.224 AC: 9297 AN: 41416

American (AMR) AF: 0.313 AC: 4787 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1170 AN: 3472

East Asian (EAS) AF: 0.559 AC: 2872 AN: 5134

South Asian (SAS) AF: 0.385 AC: 1845 AN: 4798

European-Finnish (FIN) AF: 0.303 AC: 3205 AN: 10568

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21269 AN: 67944

Other (OTH) AF: 0.321 AC: 677 AN: 2112

Alfa AF: 0.311 Hom.: 12593

Bravo AF: 0.295

Asia WGS AF: 0.460 AC: 1598 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Molecular Genetics and Enzymology, National Research Centre

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.5
DANN	Benign	0.42
PhyloP100		-0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs867858; hg19: chr8-11616338;