chr3-128485892-T-C

Position:

chr3-128485892-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_032638.5(GATA2):c.706A>G(p.Met236Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

GATA2
NM_032638.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 5.81

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 -4 ACMG points.

BS2

High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA2	NM_032638.5 linkuse as main transcript	c.706A>G	p.Met236Val	missense_variant	3/6	ENST00000341105.7	NP_116027.2	P23769-1
GATA2	NM_001145661.2 linkuse as main transcript	c.706A>G	p.Met236Val	missense_variant	4/7		NP_001139133.1	P23769-1
GATA2	NM_001145662.1 linkuse as main transcript	c.706A>G	p.Met236Val	missense_variant	3/6		NP_001139134.1	P23769-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GATA2	ENST00000341105.7 linkuse as main transcript	c.706A>G	p.Met236Val	missense_variant	3/6	1	NM_032638.5	ENSP00000345681.2	P23769-1
GATA2	ENST00000487848.6 linkuse as main transcript	c.706A>G	p.Met236Val	missense_variant	4/7	1		ENSP00000417074.1	P23769-1
GATA2	ENST00000430265.6 linkuse as main transcript	c.706A>G	p.Met236Val	missense_variant	3/6	1		ENSP00000400259.2	P23769-2
GATA2	ENST00000696466.1 linkuse as main transcript	c.988A>G	p.Met330Val	missense_variant	5/8			ENSP00000512647.1	A0A8Q3WLD0

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250898

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2023	Observed in large population cohorts (gnomAD; internal data); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with pancytopenia, lymphadenopathy, and splenomegaly (PMID: 31309983); This variant is associated with the following publications: (PMID: 31309983) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 17, 2019

This sequence change does not appear to have been previously described in patients with GATA2-related disorders and has been described in the gnomAD database with a low population frequency of 0.0080% in African subpopulation (dbSNP rs746737860). The p.Met236Val change affects a moderately conserved amino acid residue located in a domain of the GATA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met236Val substitution. Due to these evidences and the lack of functional studies, the clinical significance of the p.Met236Val change remains unknown at this time. -

Monocytopenia with susceptibility to infections

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Jul 17, 2019

This GATA2 variant (rs746737860) is rare (<0.1%) in large population datasets (gnomAD: 6/82258 total alleles; 0.002126%; no homozygotes). This variant is not described in the literature to our knowledge, and a single submitter in ClinVar classifies the sigificance of this variant as uncertain. Two bioinformatic tools queriedpredict that this substitution would be tolerated, however the methionine residue at this position is evolutionarily conserved across all species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 3 splicing, although this has not been confirmed experimentally to our knowledge. The clinical significance of c.706A>G is uncertain at this time. -

Acute myeloid leukemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 10, 2024

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.30

T;.;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.027

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.66

.;T;T

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.6

L;L;L

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.72

N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.47

T;T;T

Sift4G

Benign

0.50

T;T;T

Polyphen

0.029

B;B;B

Vest4

0.61

MutPred

0.18

Loss of glycosylation at T235 (P = 0.0142);Loss of glycosylation at T235 (P = 0.0142);Loss of glycosylation at T235 (P = 0.0142);

MVP

0.93

MPC

0.54

ClinPred

0.14

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.43

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