10-8073747-A-T

Position:

• chr10-8073747-A-T

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.1059A>T​(p.Arg353Ser) variant causes a missense change. 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R353K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA3 NM_001002295.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.45

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 short_sequence_motif YxKxHxxxRP (size 9) in uniprot entity GATA3_HUMAN there are 6 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 chr10-8073746-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 585128.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 10-8073747-A-T is Pathogenic according to our data. Variant chr10-8073747-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 16630.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-8073747-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA3	NM_001002295.2	c.1059A>T	p.Arg353Ser	missense_variant	6/6	ENST00000379328.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA3	ENST00000379328.9	c.1059A>T	p.Arg353Ser	missense_variant	6/6	1	NM_001002295.2	A1
GATA3	ENST00000346208.4	c.1056A>T	p.Arg352Ser	missense_variant	6/6	1		P4
GATA3	ENST00000461472.1	c.*4A>T		3_prime_UTR_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

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

Nov 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.4	D;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		1.0	D;D;D
Vest4		0.98
MutPred		0.87		.;.;Gain of catalytic residue at R352 (P = 0.0098);
MVP		1.0
MPC		1.9
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.97
gMVP		0.99

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: rs104894165; hg19: chr10-8115710;