10-8073738-G-C

Position:

• chr10-8073738-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001002295.2(GATA3):​c.1051-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA3 NM_001002295.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0

Genes affected

GATA3 (HGNC:4172): (GATA binding protein 3) This gene encodes a protein which belongs to the GATA family of transcription factors. The protein contains two GATA-type zinc fingers and is an important regulator of T-cell development and plays an important role in endothelial cell biology. Defects in this gene are the cause of hypoparathyroidism with sensorineural deafness and renal dysplasia. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.8, offset of 8, new splice context is: atctttgtttacattaacAGacc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-8073738-G-C is Pathogenic according to our data. Variant chr10-8073738-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 430696.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA3	NM_001002295.2	c.1051-1G>C		splice_acceptor_variant, intron_variant		ENST00000379328.9	NP_001002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA3	ENST00000379328.9	c.1051-1G>C		splice_acceptor_variant, intron_variant		1	NM_001002295.2	ENSP00000368632.3
GATA3	ENST00000346208.4	c.1048-1G>C		splice_acceptor_variant, intron_variant		1		ENSP00000341619.3
GATA3	ENST00000461472.1	c.569-1G>C		splice_acceptor_variant, intron_variant		3		ENSP00000515407.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Stage 5 chronic kidney disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Bioinformatics dept., Datar Cancer Genetics Limited, India

Nov 02, 2016

- -

GATA3-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2024

The GATA3 c.1051-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has not been reported in the literature or in a large population database indicating this variant is rare. Alternative variants at the same acceptor splice site have been observed in individuals with Hypoparathyroidism, Deafness, and Renal Dysplasia (HDR) Syndrome (1051-1G>T, Nesbit et al. 2004. PubMed ID: 14985365; c.1051-2A>G, Ali et al. 2007. PubMed ID: 17210674; c.1051-2A>G, Belge et al. 2017. PubMed ID: 27387476). Variants that disrupt the consensus splice acceptor site in GATA3 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.94	D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.67		Position offset: 9
DS_AL_spliceai		0.87		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs112417755; hg19: chr10-8115701; COSMIC: COSV60515946;