10-8064043-C-G

Variant names:

• chr10-8064043-C-G
• rs104894162
• NM_001002295.2:c.829C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001002295.2(GATA3):​c.829C>G​(p.Arg277Gly) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R277Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA3 NM_001002295.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.84
• Publications: 0 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 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001002295.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA3	NM_001002295.2	c.829C>G	p.Arg277Gly	missense_variant	Exon 4 of 6	ENST00000379328.9	NP_001002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA3	ENST00000379328.9	c.829C>G	p.Arg277Gly	missense_variant	Exon 4 of 6	1	NM_001002295.2	ENSP00000368632.3
GATA3	ENST00000346208.4	c.826C>G	p.Arg276Gly	missense_variant	Exon 4 of 6	1		ENSP00000341619.3
GATA3	ENST00000461472.1	c.442+5202C>G		intron_variant	Intron 1 of 2	3		ENSP00000515407.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	.;.;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	.;D;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;.;M
PhyloP100		2.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.2	D;.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;D;D
Vest4		0.95
MutPred		0.68		.;.;Loss of stability (P = 0.0076);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		2.1
Varity_R		0.96
gMVP		0.96
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs104894162; hg19: chr10-8106006;