rs387906632

chr3-128483868-G-Achr3-128483868-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032638.5(GATA2):c.1009C>T(p.Arg337Ter) variant causes a stop gained 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R337R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GATA2 NM_032638.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.09

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-128483868-G-A is Pathogenic according to our data. Variant chr3-128483868-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-128483868-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA2	NM_001145661.2	c.1009C>T	p.Arg337Ter	stop_gained	5/7	ENST00000487848.6
GATA2	NM_032638.5	c.1009C>T	p.Arg337Ter	stop_gained	4/6	ENST00000341105.7
GATA2	NM_001145662.1	c.1009C>T	p.Arg337Ter	stop_gained	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA2	ENST00000341105.7	c.1009C>T	p.Arg337Ter	stop_gained	4/6	1	NM_032638.5	P1
GATA2	ENST00000487848.6	c.1009C>T	p.Arg337Ter	stop_gained	5/7	1	NM_001145661.2	P1
GATA2	ENST00000430265.6	c.1009C>T	p.Arg337Ter	stop_gained	4/6	1
GATA2	ENST00000696466.1	c.1291C>T	p.Arg431Ter	stop_gained	6/8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Monocytopenia with susceptibility to infections Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Mar 23, 2023

- -

GATA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

The GATA2 c.1009C>T variant is predicted to result in premature protein termination (p.Arg337*). This variant has been reported to be causative for GATA2-related disorders including MonoMAC, and primary lymphedema and predisposition to acute myeloid leukemia (Ostergaard et al. 2011. PubMed ID: 21892158; Hsu et al. 2013. PubMed ID: 23502222). This variant is not present in a large population database (https://gnomad.broadinstitute.org/) and has been interpreted as Pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/29719/). Nonsense variants in GATA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 30, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29719). This premature translational stop signal has been observed in individual(s) with clinical features of GATA2 deficiency (PMID: 21892158, 23502222, 27894982). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg337*) in the GATA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GATA2 are known to be pathogenic (PMID: 21670465, 23223431). -

Deafness-lymphedema-leukemia syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 2011

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2023

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23502222, 33684095, 21892158, 32770553, 34529785, 30538114, 27894982, 35753512) -

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

PVS1, PS4, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.93
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs387906632; hg19: chr3-128202711; COSMIC: COSV62007611; COSMIC: COSV62007611;