Genetic Variant GATA3:p.Gly246Asp (chr10-8058800-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001002295.2(GATA3):c.737G>A(p.Gly246Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G246A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GATA3
NM_001002295.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.18

Publications

0 publications found

Variant links:

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

GATA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA3	NM_001002295.2 link	c.737G>A	p.Gly246Asp	missense_variant	Exon 3 of 6	ENST00000379328.9	NP_001002295.1	P23771-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GATA3	ENST00000379328.9 link	c.737G>A	p.Gly246Asp	missense_variant	Exon 3 of 6	1	NM_001002295.2	ENSP00000368632.3	P23771-2
GATA3	ENST00000346208.4 link	c.737G>A	p.Gly246Asp	missense_variant	Exon 3 of 6	1		ENSP00000341619.3	P23771-1
GATA3	ENST00000461472.1 link	c.401G>A	p.Gly134Asp	missense_variant	Exon 1 of 3	3		ENSP00000515407.1	A0A994J6H6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724178

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111810

Other (OTH)

AF:

0.00

AC:

AN:

60336

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

.;.;D

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.50

D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.0

M;M;M

PhyloP100

8.2

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.1

N;.;N

REVEL

Uncertain

0.57

Sift

Benign

0.12

T;.;T

Sift4G

Benign

0.51

T;.;T

Polyphen

0.70

P;P;P

Vest4

0.63

MutPred

0.28

Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);

MVP

0.79

MPC

1.2

ClinPred

0.84

GERP RS

5.5

Varity_R

0.34

gMVP

0.41

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over