3-128486911-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_032638.5(GATA2):c.121C>G(p.Pro41Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000713 in 1,612,868 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P41S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00074 ( 0 hom. )

Consequence

GATA2
NM_032638.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:6

Conservation

PhyloP100: 9.56

Publications

13 publications found

Variant links:

COSMIC-nc: COSV105909118

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.28287715).

BP6

Variant 3-128486911-G-C is Benign according to our data. Variant chr3-128486911-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241716.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000499 (76/152380) while in subpopulation NFE AF = 0.000941 (64/68042). AF 95% confidence interval is 0.000755. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_032638.5 link	c.121C>G	p.Pro41Ala	missense_variant	Exon 2 of 6	ENST00000341105.7	NP_116027.2	P23769-1
GATA2	NM_001145661.2 link	c.121C>G	p.Pro41Ala	missense_variant	Exon 3 of 7		NP_001139133.1	P23769-1
GATA2	NM_001145662.1 link	c.121C>G	p.Pro41Ala	missense_variant	Exon 2 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.121C>G	p.Pro41Ala	missense_variant	Exon 2 of 6	1	NM_032638.5	ENSP00000345681.2		P23769-1

Frequencies

GnomAD3 genomes

AF:

0.000499

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000940

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000617

AC:

151

AN:

244694

AF XY:

0.000535

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000205

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000815

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.000838

GnomAD4 exome

AF:

0.000735

AC:

1074

AN:

1460488

Hom.:

Cov.:

AF XY:

0.000679

AC XY:

493

AN XY:

726460

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33460

American (AMR)

AF:

0.000224

AC:

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26010

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

85862

European-Finnish (FIN)

AF:

0.00120

AC:

AN:

53248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000874

AC:

971

AN:

1111558

Other (OTH)

AF:

0.000381

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

133

199

266

332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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:

0.000499

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74524

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41586

American (AMR)

AF:

0.0000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000941

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000733

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000702

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 06, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal and/or family history of hematologic disease, as well as in a pediatric patient with rhabdomyosarcoma (PMID: 22533337, 29365323, 29797310, 39037077); This variant is associated with the following publications: (PMID: 29797310, 31256874, 24754962, 25624456, 29365323, 27930734, 22533337, 33386779, 26445707, 39037077) -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GATA2: BS1, BS2 -

Deafness-lymphedema-leukemia syndrome

Uncertain:2

Oct 31, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A GATA2 c.121C>G (p.Pro41Ala) variant was identified at a near heterozygous allelic fraction of 49.58%, a frequency which may be consistent with it being of germline origin. This variant has been reported in a germline state in one individual affected with pediatric soft tissue sarcoma (Yndestad S et al., PMID: 39037077) and in three individuals affected with hematologic conditions (Kager L et al., PMID: 29797310; Drazer MW et al., PMID: 29365323; Holme H et al., PMID: 22533337). The GATA2 c.121C>G (p.Pro41Ala) variant has been reported in the ClinVar database with conflicting classifications of pathogenicity (uncertain significance by 3 submitters; likely benign by 3 submitters and benign by 1 submitter). The highest population minor allele frequency in the population database genome aggregation database (v4.1.0) is 0.1080% in the European (Finnish) population. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GATA2 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant classified as being of uncertain clinical significance. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:2

Jun 28, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GATA2-related disorder

Uncertain:1

Jan 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The GATA2 c.121C>G variant is predicted to result in the amino acid substitution p.Pro41Ala. This variant was reported in an individual with myelodysplastic syndrome (Holme et al. 2012. PubMed ID: 22533337), as well as in an individual with leukopenia characterized by moderate neutropenia and B cell deficiency (Kager et al. 2018. PubMed ID: 29797310); however not enough information was provided in either report to establish pathogenicity. This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/241716/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jul 14, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Monocytopenia with susceptibility to infections

Benign:1

Jul 07, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 20, 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.75

D;.;D;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

.;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

1.7

L;L;L;.

PhyloP100

9.6

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.2

N;N;N;D

REVEL

Pathogenic

0.72

Sift

Benign

0.39

T;T;T;T

Sift4G

Benign

0.70

T;T;T;T

Polyphen

0.47

P;D;P;.

Vest4

0.64

MVP

0.85

MPC

1.4

ClinPred

0.086

GERP RS

4.6

Varity_R

0.29

gMVP

0.56

Mutation Taster

=69/31

polymorphism

(source)

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

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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