dbSNP rs777726701: GATA2:p.Gly468Cys (chr3-128481060-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032638.5(GATA2):c.1402G>T(p.Gly468Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,542 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GATA2
NM_032638.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.29

Variant links:

Genes affected

GATA2 (HGNC:4171): (GATA binding protein 2) This gene encodes a member of the GATA family of zinc-finger transcription factors that are named for the consensus nucleotide sequence they bind in the promoter regions of target genes. The encoded protein plays an essential role in regulating transcription of genes involved in the development and proliferation of hematopoietic and endocrine cell lineages. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]

GATA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
GATA2	NM_032638.5 link	c.1402G>T	p.Gly468Cys	missense_variant	Exon 6 of 6	ENST00000341105.7	NP_116027.2	P23769-1
GATA2	NM_001145661.2 link	c.1402G>T	p.Gly468Cys	missense_variant	Exon 7 of 7		NP_001139133.1	P23769-1
GATA2	NM_001145662.1 link	c.1360G>T	p.Gly454Cys	missense_variant	Exon 6 of 6		NP_001139134.1	P23769-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7 link	c.1402G>T	p.Gly468Cys	missense_variant	Exon 6 of 6	1	NM_032638.5	ENSP00000345681.2		P23769-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1446542

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

717084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000759

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1402G>T (p.G468C) alteration is located in exon 6 (coding exon 5) of the GATA2 gene. This alteration results from a G to T substitution at nucleotide position 1402, causing the glycine (G) at amino acid position 468 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

M;.;M

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.50

Sift

Uncertain

0.0050

D;D;D

Sift4G

Benign

0.074

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.46

MutPred

0.14

Loss of glycosylation at P470 (P = 0.0411);.;Loss of glycosylation at P470 (P = 0.0411);

MVP

0.83

MPC

0.65

ClinPred

0.93

GERP RS

4.4

Varity_R

0.40

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over