3-128481880-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_032638.5(GATA2):​c.1082G>A​(p.Arg361His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging 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. R361C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

GATA2
NM_032638.5 missense

Scores

17
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.84

Publications

2 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

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_032638.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-128481881-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 472431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 3-128481880-C-T is Pathogenic according to our data. Variant chr3-128481880-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1184156.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GATA2NM_032638.5 linkc.1082G>A p.Arg361His missense_variant Exon 5 of 6 ENST00000341105.7 NP_116027.2 P23769-1
GATA2NM_001145661.2 linkc.1082G>A p.Arg361His missense_variant Exon 6 of 7 NP_001139133.1 P23769-1
GATA2NM_001145662.1 linkc.1040G>A p.Arg347His missense_variant Exon 5 of 6 NP_001139134.1 P23769-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GATA2ENST00000341105.7 linkc.1082G>A p.Arg361His missense_variant Exon 5 of 6 1 NM_032638.5 ENSP00000345681.2 P23769-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Mar 12, 2025
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1082G>A (p.R361H) alteration is located in exon 5 (coding exon 4) of the GATA2 gene. This alteration results from a G to A substitution at nucleotide position 1082, causing the arginine (R) at amino acid position 361 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in individuals with features consistent with GATA2 deficiency syndrome (Bluteau, 2018; Galera, 2018; Jung, 2018; McReynolds, 2019; Wlodarski, 2016; Zhang, 2015). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely 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

PS4, PM1, PM2, PM5, PP3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.99
D;.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.99
.;D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Pathogenic
4.2
H;.;H
PhyloP100
7.8
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-4.7
D;D;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.98
MutPred
0.92
Loss of glycosylation at T357 (P = 0.0434);.;Loss of glycosylation at T357 (P = 0.0434);
MVP
0.99
MPC
3.4
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.93
gMVP
0.98
Mutation Taster
=2/98
disease causing

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

Other links and lift over

dbSNP: rs387906634; hg19: chr3-128200723; COSMIC: COSV62003019; COSMIC: COSV62003019; API