rs387906629

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001145661.2(GATA2):c.1192C>T(p.Arg398Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GATA2
NM_001145661.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.11

Publications

43 publications found

Variant links:

COSMIC-nc: COSV62004597

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 Gene-Disease associations (from GenCC):

deafness-lymphedema-leukemia syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
GATA2 deficiency with susceptibility to MDS/AML
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
monocytopenia with susceptibility to infections
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
acute myeloid leukemia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
myelodysplastic syndrome
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

GATA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_001145661.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-128481269-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 938037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

PP5

Variant 3-128481270-G-A is Pathogenic according to our data. Variant chr3-128481270-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GATA2	NM_001145661.2 link	c.1192C>T	p.Arg398Trp	missense_variant	Exon 7 of 7	ENST00000487848.6	NP_001139133.1
GATA2	NM_032638.5 link	c.1192C>T	p.Arg398Trp	missense_variant	Exon 6 of 6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145662.1 link	c.1150C>T	p.Arg384Trp	missense_variant	Exon 6 of 6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7 link	c.1192C>T	p.Arg398Trp	missense_variant	Exon 6 of 6	1	NM_032638.5	ENSP00000345681.2
GATA2	ENST00000487848.6 link	c.1192C>T	p.Arg398Trp	missense_variant	Exon 7 of 7	1	NM_001145661.2	ENSP00000417074.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2016

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 10, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31106410, 23365458, 26264606, 29724903, 28485484, 36357187, 37216690, 28104920, 34233447, 35753512, 33417088, 26702063, 25359990, 20040766, 21242295, 31256854, 24077845, 30578959, 24345756, 24227816, 23502222, 21810969, 8701948, 30714451, 21670465, 34529785, 26492932, 21765025, 29882021, 34576178) -

Apr 13, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM1, PM2_supporting, PS3, PS4 -

Monocytopenia with susceptibility to infections

Pathogenic:2

Feb 17, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PM1, PM2, PM5, PP2, PP3, PP5 -

Sep 08, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Leukemia, acute myeloid, susceptibility to

Pathogenic:1

Jun 14, 2016

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Dec 15, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R398W pathogenic mutation (also known as c.1192C>T), located in coding exon 5 of the GATA2 gene, results from a C to T substitution at nucleotide position 1192. The arginine at codon 398 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been detected in multiple unrelated individuals with GATA2 deficiency syndrome (Dickinson RE et al. Blood, 2011 Sep;118:2656-8; Hsu AP et al. Blood, 2011 Sep;118:2653-5; Churpek JE et al. Blood, 2015 Nov;126:2484-90; Mardahl M et al. Br J Haematol, 2019 Aug;186:471-476; West RR et al. Blood Adv, 2022 Feb;6:793-807). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 398 of the GATA2 protein (p.Arg398Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with GATA2 deficiency (PMID: 21670465, 21765025). ClinVar contains an entry for this variant (Variation ID: 29709). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GATA2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GATA2 function (PMID: 29882021). For these reasons, this variant has been classified as Pathogenic. -

Deafness-lymphedema-leukemia syndrome;CN300066:GATA2 deficiency with susceptibility to MDS/AML

Pathogenic:1

Jul 06, 2021

Molecular Pathology Research Laboratory, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

PS3, PS4, PM1, PM2, PM5, PP1_Moderate, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;.;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

.;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.1

M;.;M

PhyloP100

4.1

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.2

D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.92

MutPred

0.51

Gain of glycosylation at S401 (P = 0.0062);.;Gain of glycosylation at S401 (P = 0.0062);

MVP

0.98

MPC

3.1

ClinPred

1.0

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.89

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over