10-8073747-A-T

Variant names:

• chr10-8073747-A-T
• rs104894165
• NM_001002295.2:c.1059A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. 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
• Publications: 7 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: Likely_pathogenic. The variant received 9 ACMG points.

• 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 VariationId 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 VariationId is 16630.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002295.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA3	NM_001002295.2	MANE Select	c.1059A>T	p.Arg353Ser	missense	Exon 6 of 6	NP_001002295.1
	GATA3	NM_001441115.1		c.1059A>T	p.Arg353Ser	missense	Exon 6 of 6	NP_001428044.1
	GATA3	NM_001441116.1		c.1059A>T	p.Arg353Ser	missense	Exon 7 of 7	NP_001428045.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA3	ENST00000379328.9	TSL:1 MANE Select	c.1059A>T	p.Arg353Ser	missense	Exon 6 of 6	ENSP00000368632.3
	GATA3	ENST00000346208.4	TSL:1	c.1056A>T	p.Arg352Ser	missense	Exon 6 of 6	ENSP00000341619.3
	GATA3	ENST00000461472.1	TSL:3	c.*4A>T		3_prime_UTR	Exon 3 of 3	ENSP00000515407.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hypoparathyroidism, deafness, renal disease syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894165; hg19: chr10-8115710;