rs138688940

chr3-128485941-C-Achr3-128485941-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032638.5(GATA2):c.657G>T(p.Glu219Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E219E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08317363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA2	NM_001145661.2	c.657G>T	p.Glu219Asp	missense_variant	4/7	ENST00000487848.6
GATA2	NM_032638.5	c.657G>T	p.Glu219Asp	missense_variant	3/6	ENST00000341105.7
GATA2	NM_001145662.1	c.657G>T	p.Glu219Asp	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA2	ENST00000341105.7	c.657G>T	p.Glu219Asp	missense_variant	3/6	1	NM_032638.5	P1
GATA2	ENST00000487848.6	c.657G>T	p.Glu219Asp	missense_variant	4/7	1	NM_001145661.2	P1
GATA2	ENST00000430265.6	c.657G>T	p.Glu219Asp	missense_variant	3/6	1
GATA2	ENST00000696466.1	c.939G>T	p.Glu313Asp	missense_variant	5/8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 219 of the GATA2 protein (p.Glu219Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GATA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1052524). 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. In 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	6.9
Dann	Benign	0.86
DEOGEN2	Benign	0.28	T;.;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.65	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.76	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.76	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.19
MutPred		0.18		Gain of glycosylation at S220 (P = 0.0114);Gain of glycosylation at S220 (P = 0.0114);Gain of glycosylation at S220 (P = 0.0114);
MVP		0.45
MPC		0.48
ClinPred		0.12	T
GERP RS		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.055
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr3-128204784; COSMIC: COSV100350963; COSMIC: COSV100350963;