rs745726293

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_032638.5(GATA2):c.593C>T(p.Ala198Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A198S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

GATA2
NM_032638.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.41

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.39789987).

BS2

High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GATA2	NM_001145661.2 linkuse as main transcript	c.593C>T	p.Ala198Val	missense_variant	4/7	ENST00000487848.6
GATA2	NM_032638.5 linkuse as main transcript	c.593C>T	p.Ala198Val	missense_variant	3/6	ENST00000341105.7
GATA2	NM_001145662.1 linkuse as main transcript	c.593C>T	p.Ala198Val	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA2	ENST00000341105.7 linkuse as main transcript	c.593C>T	p.Ala198Val	missense_variant	3/6	1	NM_032638.5	P1	P23769-1
GATA2	ENST00000487848.6 linkuse as main transcript	c.593C>T	p.Ala198Val	missense_variant	4/7	1	NM_001145661.2	P1	P23769-1
GATA2	ENST00000430265.6 linkuse as main transcript	c.593C>T	p.Ala198Val	missense_variant	3/6	1			P23769-2
GATA2	ENST00000696466.1 linkuse as main transcript	c.875C>T	p.Ala292Val	missense_variant	5/8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250950

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 198 of the GATA2 protein (p.Ala198Val). This variant is present in population databases (rs745726293, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with GATA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 539714). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GATA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Aug 18, 2021

- -

Acute myeloid leukemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Uncertain

0.010

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.;T

Eigen

Benign

-0.014

Eigen_PC

Benign

-0.0020

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

0.55

N;N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.2

N;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.38

B;D;B

Vest4

0.49

MutPred

0.20

Loss of glycosylation at P193 (P = 0.0207);Loss of glycosylation at P193 (P = 0.0207);Loss of glycosylation at P193 (P = 0.0207);

MVP

0.86

MPC

1.4

ClinPred

0.20

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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