rs750384699

chr3-128486142-G-Cchr3-128486142-G-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.456C>G(p.Ser152Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S152N) has been classified 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: 1.32

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=0.23066485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA2	NM_001145661.2	c.456C>G	p.Ser152Arg	missense_variant	4/7	ENST00000487848.6
GATA2	NM_032638.5	c.456C>G	p.Ser152Arg	missense_variant	3/6	ENST00000341105.7
GATA2	NM_001145662.1	c.456C>G	p.Ser152Arg	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA2	ENST00000341105.7	c.456C>G	p.Ser152Arg	missense_variant	3/6	1	NM_032638.5	P1
GATA2	ENST00000487848.6	c.456C>G	p.Ser152Arg	missense_variant	4/7	1	NM_001145661.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 24, 2020

This variant has not been reported in the literature in individuals 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) performed at Invitae indicates that this missense variant is not expected to disrupt GATA2 protein function. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 152 of the GATA2 protein (p.Ser152Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	3.6
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Uncertain	0.073	D
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.36	T;T;T
Polyphen		0.45	B;B;B
Vest4		0.48
MutPred		0.39		Gain of methylation at S152 (P = 0.0058);Gain of methylation at S152 (P = 0.0058);Gain of methylation at S152 (P = 0.0058);
MVP		0.58
MPC		0.62
ClinPred		0.41	T
GERP RS		-0.88
Varity_R		0.092
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs750384699; hg19: chr3-128204985;