3-128481849-G-C

Position:

• chr3-128481849-G-C

Variant summary

Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM2 PP3_Strong PP5_Very_Strong

The ENST00000341105.7(GATA2):​c.1113C>G​(p.Asn371Lys) variant causes a missense change. 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. N371N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GATA2 ENST00000341105.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.93

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 Pathogenic. Variant got 24 ACMG points.

• PS1: Transcript ENST00000341105.7 (GATA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 216931
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000341105.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 3-128481849-G-C is Pathogenic according to our data. Variant chr3-128481849-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1184162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-128481849-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA2	NM_001145661.2	c.1113C>G	p.Asn371Lys	missense_variant	6/7	ENST00000487848.6	NP_001139133.1
GATA2	NM_032638.5	c.1113C>G	p.Asn371Lys	missense_variant	5/6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145662.1	c.1071C>G	p.Asn357Lys	missense_variant	5/6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.1113C>G	p.Asn371Lys	missense_variant	5/6	1	NM_032638.5	ENSP00000345681	P1
GATA2	ENST00000487848.6	c.1113C>G	p.Asn371Lys	missense_variant	6/7	1	NM_001145661.2	ENSP00000417074	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 371 of the GATA2 protein (p.Asn371Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with GATA2-related conditions and/or myelodysplastic syndrome (PMID: 21670465, 24077845, 26702063; Invitae). ClinVar contains an entry for this variant (Variation ID: 1184162). 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 expected to disrupt GATA2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Deafness-lymphedema-leukemia syndrome;CN300066:GATA2 deficiency with susceptibility to MDS/AML Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Molecular Pathology Research Laboratory, SA Pathology

Jul 06, 2021

PS1, PS4_Moderate, PM1, PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	5.1	H;.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.98
MutPred		0.89		Gain of methylation at N371 (P = 0.003);.;Gain of methylation at N371 (P = 0.003);
MVP		0.98
MPC		3.3
ClinPred		1.0	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		1.0

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: chr3-128200692;