rs146116228

Variant names:

• chr3-128485924-C-A
• rs146116228
• NM_001145661.2:c.674G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-128485924-C-A
• chr3-128485924-C-G
• chr3-128485924-C-T

Variant summary

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

The NM_001145661.2(GATA2):​c.674G>T​(p.Ser225Ile) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S225N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA2 NM_001145661.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90
• Publications: 4 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=0.23556629).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_001145661.2	c.674G>T	p.Ser225Ile	missense_variant	Exon 4 of 7	ENST00000487848.6	NP_001139133.1
GATA2	NM_032638.5	c.674G>T	p.Ser225Ile	missense_variant	Exon 3 of 6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145662.1	c.674G>T	p.Ser225Ile	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.674G>T	p.Ser225Ile	missense_variant	Exon 3 of 6	1	NM_032638.5	ENSP00000345681.2
GATA2	ENST00000487848.6	c.674G>T	p.Ser225Ile	missense_variant	Exon 4 of 7	1	NM_001145661.2	ENSP00000417074.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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 08, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with isoleucine at codon 225 of the GATA2 protein (p.Ser225Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	Benign	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;.;D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.4	L;L;L
PhyloP100		1.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.083	T;T;T
Sift4G	Uncertain	0.049	D;T;D
Polyphen		0.042	B;B;B
Vest4		0.45
MutPred		0.34		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		0.58
MPC		0.72
ClinPred		0.72	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.36
Mutation Taster		=75/25	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: rs146116228; hg19: chr3-128204767;