rs1553771139

Variant names:

• chr3-128486893-C-T
• rs1553771139
• NM_001145661.2:c.139G>A

Variant summary

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

The NM_001145661.2(GATA2):​c.139G>A​(p.Val47Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,248 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V47G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GATA2 NM_001145661.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_001145661.2	c.139G>A	p.Val47Ile	missense_variant	Exon 3 of 7	ENST00000487848.6	NP_001139133.1
GATA2	NM_032638.5	c.139G>A	p.Val47Ile	missense_variant	Exon 2 of 6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145662.1	c.139G>A	p.Val47Ile	missense_variant	Exon 2 of 6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.139G>A	p.Val47Ile	missense_variant	Exon 2 of 6	1	NM_032638.5	ENSP00000345681.2
GATA2	ENST00000487848.6	c.139G>A	p.Val47Ile	missense_variant	Exon 3 of 7	1	NM_001145661.2	ENSP00000417074.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460248 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726264

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111530

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 33

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

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 47 of the GATA2 protein (p.Val47Ile). 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: 539709). 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;D;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.0	.;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M;M;M;.
PhyloP100		2.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.55	N;N;N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Benign	0.10	T;T;T;D
Vest4		0.43
ClinPred		0.94	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.41
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1553771139; hg19: chr3-128205736;