10-8064043-C-T

Position:

• chr10-8064043-C-T

Variant summary

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

The NM_001002295.2(GATA3):​c.829C>T​(p.Arg277Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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: 32)
• Consequence: GATA3 NM_001002295.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.84

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: 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 10-8064043-C-T is Pathogenic according to our data. Variant chr10-8064043-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16623.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-8064043-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA3	NM_001002295.2	c.829C>T	p.Arg277Ter	stop_gained	4/6	ENST00000379328.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA3	ENST00000379328.9	c.829C>T	p.Arg277Ter	stop_gained	4/6	1	NM_001002295.2	A1
GATA3	ENST00000346208.4	c.826C>T	p.Arg276Ter	stop_gained	4/6	1		P4
GATA3	ENST00000461472.1	c.443+5202C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 07, 2023

This sequence change creates a premature translational stop signal (p.Arg277*) in the GATA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GATA3 are known to be pathogenic (PMID: 14985365, 21242646). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypoparathyroidism, sensorineural deafness, renal anomaly syndrome (PMID: 10935639). ClinVar contains an entry for this variant (Variation ID: 16623). For these reasons, this variant has been classified as Pathogenic. -

Hypoparathyroidism, deafness, renal disease syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 27, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.72	D
MutationTaster	Benign	1.0	A;A
Vest4		0.98
GERP RS		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs104894162; hg19: chr10-8106006;