8-11757212-C-T

Position:

• chr8-11757212-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001308093.3(GATA4):​c.1149+129C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,375,922 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (49 hom.)
• Consequence: GATA4 NM_001308093.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: -2.78

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=-0.83).
• BP6: Variant 8-11757212-C-T is Benign according to our data. Variant chr8-11757212-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 433022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1695/152344) while in subpopulation AFR AF= 0.0352 (1462/41570). AF 95% confidence interval is 0.0337. There are 34 homozygotes in gnomad4. There are 866 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1695 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA4	NM_001308093.3	c.1149+129C>T		intron_variant		ENST00000532059.6	NP_001295022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6	c.1149+129C>T		intron_variant		1	NM_001308093.3	ENSP00000435712	A1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1695 AN: 152226 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00267 AC: 3263 AN: 1223578 Hom.: 49 AF XY: 0.00306 AC XY: 1839 AN XY: 600356

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.000887

Gnomad4 EAS exome AF: 0.00800

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.0000502

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.0111 AC: 1695 AN: 152344 Hom.: 34 Cov.: 33 AF XY: 0.0116 AC XY: 866 AN XY: 74504

Gnomad4 AFR AF: 0.0352

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.0219

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.000483 Hom.: 0

Bravo AF: 0.0120

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital heart disease Pathogenic:1 Benign:1

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_008177.2(NM_002052.4):c.1146+129C>T in the GATA4 gene has an allele frequency of 0.034 in African subpopulation in the gnomAD database. 8 homozygous occurrences are observed in the gnomAD database. Benign computational verdict because benign prediction from DANN. Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2, BP4. -
Pathogenic, no assertion criteria provided	clinical testing	Central Research Laboratory, Sri Devaraj Urs Academy of Higher Education and Research	Jan 07, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 09, 2021

The c.1146+129C>T variant in GATA4 is classified as benign because it has been identified in 3.38% (294/8710) of African/African-American chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP codes applied: BA1 -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.64

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

LitVar

Other links and lift over

dbSNP: rs116052854; hg19: chr8-11614721;