rs12458

Variant names:

• chr8-11759731-A-T
• rs12458
• NM_001308093.3:c.*1256A>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001308093.3(GATA4):​c.*1256A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 152,118 control chromosomes in the GnomAD database, including 9,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9410 hom., cov: 33)
  • Exomes 𝑓: 0.35 (4 hom.)
• Consequence: GATA4 NM_001308093.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: -0.411

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 8-11759731-A-T is Benign according to our data. Variant chr8-11759731-A-T is described in ClinVar as [Benign]. Clinvar id is 433026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11759731-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA4	NM_001308093.3	c.*1256A>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000532059.6	NP_001295022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6	c.*1256A>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_001308093.3	ENSP00000435712.1
GATA4	ENST00000335135.8	c.*1256A>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000334458.4
GATA4	ENST00000622443.3	c.*1256A>T		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000482268.2
GATA4	ENST00000528712.5	c.*1256A>T		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000435043.1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52820 AN: 151896 Hom.: 9401 Cov.: 33

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.364

GnomAD4 exome AF: 0.346 AC: 36 AN: 104 Hom.: 4 Cov.: 0 AF XY: 0.368 AC XY: 28 AN XY: 76

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.500

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.346

Gnomad4 NFE exome AF: 0.323

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.348 AC: 52863 AN: 152014 Hom.: 9410 Cov.: 33 AF XY: 0.350 AC XY: 25984 AN XY: 74288

Gnomad4 AFR AF: 0.382

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.537

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.363

Alfa AF: 0.335 Hom.: 5036

Bravo AF: 0.351

Asia WGS AF: 0.462 AC: 1602 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital heart disease Pathogenic:1 Benign:1

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

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

NM_002052.3:c.*1256A>T in the gene GATA4 has an allele frequency of 0.376 in African subpopulation in the gnomAD database. 1936 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1; BS2. -

not provided Benign:2

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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 0.375, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.2
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs12458; hg19: chr8-11617240;