10-8073787-C-T

Variant names:

• chr10-8073787-C-T
• rs104894164
• NM_001002295.2:c.1099C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001002295.2(GATA3):​c.1099C>T​(p.Arg367*) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA3 NM_001002295.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.42
• Publications: 12 publications found

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]

GATA3 Gene-Disease associations (from GenCC):

• hypoparathyroidism-deafness-renal disease syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-8073787-C-T is Pathogenic according to our data. Variant chr10-8073787-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA3	NM_001002295.2	c.1099C>T	p.Arg367*	stop_gained	Exon 6 of 6	ENST00000379328.9	NP_001002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA3	ENST00000379328.9	c.1099C>T	p.Arg367*	stop_gained	Exon 6 of 6	1	NM_001002295.2	ENSP00000368632.3
GATA3	ENST00000346208.4	c.1096C>T	p.Arg366*	stop_gained	Exon 6 of 6	1		ENSP00000341619.3
GATA3	ENST00000461472.1	c.*44C>T		3_prime_UTR_variant	Exon 3 of 3	3		ENSP00000515407.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypoparathyroidism, deafness, renal disease syndrome Pathogenic:3

Feb 15, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease in this gene and is associated with hypoparathyroidism, sensorineural deafness, and renal dysplasia (MIM#146255). In addition, dominant-negative has been proven for a single missense variant (PMID: 21120445). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - This variant is known to have variable expressivity (PMID: 26316437, 30534854). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant results in the loss of the annotated DNA binding residue (NCBI). (I) 0704 - Another protein truncating variant (PTV) comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(His380Glnfs*5) has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed multiple times as de novo in patients with hypoparathyroidism, sensorineural deafness and renal dysplasia (ClinVar, PMID: 26316437, 30534854, 11389161). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 01, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with GATA3-related disorder (ClinVar ID: VCV000016626/ PMID: 11389161). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Jul 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg367*) in the GATA3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the GATA3 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome (PMID: 11389161, 25137426, 26316437, 30534854). ClinVar contains an entry for this variant (Variation ID: 16626). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 04, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 78 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11389161, 23757620, 26777049, 17309062, 28303854, 14985365, 19253381, 26384470, 30534854, 26316437, 24077912) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Benign	0.76	D
PhyloP100		2.4
Vest4		0.93
GERP RS		5.3
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs104894164; hg19: chr10-8115750;