chr3-128486057-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032638.5(GATA2):​c.541G>C​(p.Val181Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GATA2
NM_032638.5 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.42
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GATA2NM_001145661.2 linkuse as main transcriptc.541G>C p.Val181Leu missense_variant 4/7 ENST00000487848.6 NP_001139133.1
GATA2NM_032638.5 linkuse as main transcriptc.541G>C p.Val181Leu missense_variant 3/6 ENST00000341105.7 NP_116027.2
GATA2NM_001145662.1 linkuse as main transcriptc.541G>C p.Val181Leu missense_variant 3/6 NP_001139134.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GATA2ENST00000341105.7 linkuse as main transcriptc.541G>C p.Val181Leu missense_variant 3/61 NM_032638.5 ENSP00000345681 P1P23769-1
GATA2ENST00000487848.6 linkuse as main transcriptc.541G>C p.Val181Leu missense_variant 4/71 NM_001145661.2 ENSP00000417074 P1P23769-1
GATA2ENST00000430265.6 linkuse as main transcriptc.541G>C p.Val181Leu missense_variant 3/61 ENSP00000400259 P23769-2
GATA2ENST00000696466.1 linkuse as main transcriptc.823G>C p.Val275Leu missense_variant 5/8 ENSP00000512647

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 23, 2020In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GATA2 protein function. This variant has not been reported in the literature in individuals with GATA2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 181 of the GATA2 protein (p.Val181Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.48
T;.;T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.94
.;D;D
M_CAP
Pathogenic
0.53
D
MetaRNN
Uncertain
0.58
D;D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Uncertain
2.3
M;M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.1
N;N;N
REVEL
Pathogenic
0.65
Sift
Benign
0.067
T;T;T
Sift4G
Benign
0.21
T;T;T
Polyphen
0.86
P;B;P
Vest4
0.62
MutPred
0.23
Loss of glycosylation at P178 (P = 0.0127);Loss of glycosylation at P178 (P = 0.0127);Loss of glycosylation at P178 (P = 0.0127);
MVP
0.83
MPC
1.3
ClinPred
0.97
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.43
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-128204900; API