3-128486108-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001145661.2(GATA2):c.490G>A(p.Ala164Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,612,430 control chromosomes in the GnomAD database, including 24,238 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A164S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 2722 hom., cov: 32)

Exomes 𝑓: 0.17 ( 21516 hom. )

Consequence

GATA2
NM_001145661.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 0.635

Publications

66 publications found

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 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036796033).

BP6

Variant 3-128486108-C-T is Benign according to our data. Variant chr3-128486108-C-T is described in ClinVar as Benign. ClinVar VariationId is 134467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GATA2	NM_001145661.2 link	c.490G>A	p.Ala164Thr	missense_variant	Exon 4 of 7	ENST00000487848.6	NP_001139133.1
GATA2	NM_032638.5 link	c.490G>A	p.Ala164Thr	missense_variant	Exon 3 of 6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145662.1 link	c.490G>A	p.Ala164Thr	missense_variant	Exon 3 of 6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7 link	c.490G>A	p.Ala164Thr	missense_variant	Exon 3 of 6	1	NM_032638.5	ENSP00000345681.2
GATA2	ENST00000487848.6 link	c.490G>A	p.Ala164Thr	missense_variant	Exon 4 of 7	1	NM_001145661.2	ENSP00000417074.1

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27616

AN:

151970

Hom.:

2719

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.215

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.179

Gnomad FIN

AF:

0.182

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.156

Gnomad OTH

AF:

0.183

GnomAD2 exomes

AF:

0.198

AC:

48692

AN:

245488

AF XY:

0.194

show subpopulations

Gnomad AFR exome

AF:

0.180

Gnomad AMR exome

AF:

0.274

Gnomad ASJ exome

AF:

0.230

Gnomad EAS exome

AF:

0.379

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.154

Gnomad OTH exome

AF:

0.188

GnomAD4 exome

AF:

0.166

AC:

241798

AN:

1460340

Hom.:

21516

Cov.:

AF XY:

0.166

AC XY:

120739

AN XY:

726352

show subpopulations

African (AFR)

AF:

0.184

AC:

6161

AN:

33468

American (AMR)

AF:

0.271

AC:

12040

AN:

44468

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

6075

AN:

26098

East Asian (EAS)

AF:

0.367

AC:

14549

AN:

39648

South Asian (SAS)

AF:

0.186

AC:

16019

AN:

86024

European-Finnish (FIN)

AF:

0.181

AC:

9626

AN:

53098

Middle Eastern (MID)

AF:

0.228

AC:

1286

AN:

5652

European-Non Finnish (NFE)

AF:

0.149

AC:

165070

AN:

1111576

Other (OTH)

AF:

0.182

AC:

10972

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

13765

27530

41294

55059

68824

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6076

12152

18228

24304

30380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.182

AC:

27648

AN:

152090

Hom.:

2722

Cov.:

AF XY:

0.185

AC XY:

13775

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.183

AC:

7589

AN:

41498

American (AMR)

AF:

0.215

AC:

3285

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

799

AN:

3470

East Asian (EAS)

AF:

0.379

AC:

1949

AN:

5140

South Asian (SAS)

AF:

0.179

AC:

861

AN:

4822

European-Finnish (FIN)

AF:

0.182

AC:

1929

AN:

10596

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.156

AC:

10615

AN:

67966

Other (OTH)

AF:

0.187

AC:

394

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1158

2317

3475

4634

5792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

298

596

894

1192

1490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.166

Hom.:

4888

Bravo

AF:

0.188

TwinsUK

AF:

0.152

AC:

563

ALSPAC

AF:

0.138

AC:

533

ESP6500AA

AF:

0.167

AC:

736

ESP6500EA

AF:

0.162

AC:

1395

ExAC

AF:

0.192

AC:

23228

Asia WGS

AF:

0.236

AC:

823

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7Other:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 44% of patients studied by a panel of primary immunodeficiencies. Number of patients: 42. Only high quality variants are reported.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Nov 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327, 16934006, 27153395)

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Deafness-lymphedema-leukemia syndrome

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Monocytopenia with susceptibility to infections

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Oct 18, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.0

.;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

0.64

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.53

N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.17

T;T;T

Vest4

0.11

ClinPred

0.0034

GERP RS

1.8

Varity_R

0.071

gMVP

0.36

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over