3-128485866-G-T

Variant names:

• chr3-128485866-G-T
• NM_032638.5:c.732C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032638.5(GATA2):​c.732C>A​(p.His244Gln) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_032638.5	c.732C>A	p.His244Gln	missense_variant	Exon 3 of 6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145661.2	c.732C>A	p.His244Gln	missense_variant	Exon 4 of 7		NP_001139133.1
GATA2	NM_001145662.1	c.732C>A	p.His244Gln	missense_variant	Exon 3 of 6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.732C>A	p.His244Gln	missense_variant	Exon 3 of 6	1	NM_032638.5	ENSP00000345681.2
GATA2	ENST00000487848.6	c.732C>A	p.His244Gln	missense_variant	Exon 4 of 7	1		ENSP00000417074.1
GATA2	ENST00000430265.6	c.732C>A	p.His244Gln	missense_variant	Exon 3 of 6	1		ENSP00000400259.2
GATA2	ENST00000696466.1	c.1014C>A	p.His338Gln	missense_variant	Exon 5 of 8			ENSP00000512647.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with glutamine at codon 244 of the GATA2 protein (p.His244Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.035	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.90	P;D;P
Vest4		0.88
MutPred		0.17		Gain of glycosylation at Y249 (P = 0.024);Gain of glycosylation at Y249 (P = 0.024);Gain of glycosylation at Y249 (P = 0.024);
MVP		0.84
MPC		1.4
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.66
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-128204709;