3-128481230-G-T

Variant names:

• chr3-128481230-G-T
• rs374457534
• NM_032638.5:c.1232C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032638.5(GATA2):​c.1232C>A​(p.Ala411Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A411V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.19
• Publications: 5 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.104902804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_032638.5	c.1232C>A	p.Ala411Glu	missense_variant	Exon 6 of 6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145661.2	c.1232C>A	p.Ala411Glu	missense_variant	Exon 7 of 7		NP_001139133.1
GATA2	NM_001145662.1	c.1190C>A	p.Ala397Glu	missense_variant	Exon 6 of 6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.1232C>A	p.Ala411Glu	missense_variant	Exon 6 of 6	1	NM_032638.5	ENSP00000345681.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A411E variant (also known as c.1232C>A), located in coding exon 5 of the GATA2 gene, results from a C to A substitution at nucleotide position 1232. The alanine at codon 411 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

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

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with GATA2-related conditions. 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GATA2 protein function. ClinVar contains an entry for this variant (Variation ID: 642823). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 411 of the GATA2 protein (p.Ala411Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.29	T;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.64	.;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.75	N;.;N
PhyloP100		6.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.59	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.81	T;T;T
Sift4G	Benign	0.65	T;T;T
Polyphen		0.013	B;P;B
Vest4		0.18
MutPred		0.19		Gain of glycosylation at S407 (P = 0.0122);.;Gain of glycosylation at S407 (P = 0.0122);
MVP		0.64
MPC		0.17
ClinPred		0.48	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.65
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs374457534; hg19: chr3-128200073;