rs104894163

Positions:

• chr10-8064037-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001002295.2(GATA3):​c.823T>A​(p.Trp275Arg) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W275L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA3 NM_001002295.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

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 11 ACMG points.

• PM1: In a zinc_finger_region GATA-type 1 (size 24) in uniprot entity GATA3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001002295.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-8064038-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 10-8064037-T-A is Pathogenic according to our data. Variant chr10-8064037-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 16624.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-8064037-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA3	NM_001002295.2	c.823T>A	p.Trp275Arg	missense_variant	4/6	ENST00000379328.9	NP_001002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA3	ENST00000379328.9	c.823T>A	p.Trp275Arg	missense_variant	4/6	1	NM_001002295.2	ENSP00000368632.3
GATA3	ENST00000346208.4	c.820T>A	p.Trp274Arg	missense_variant	4/6	1		ENSP00000341619.3
GATA3	ENST00000461472.1	c.442+5196T>A		intron_variant		3		ENSP00000515407.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypoparathyroidism, deafness, renal disease syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.3	.;.;H
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-13	D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;D;D
Vest4		0.98
MutPred		0.87		.;.;Gain of disorder (P = 0.0014);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.97

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: rs104894163; hg19: chr10-8106000;