rs1553770510

Positions:

• chr3-128481878-G-A
• chr3-128481878-G-C

Variant summary

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

The ENST00000341105.7(GATA2):​c.1084C>T​(p.Arg362Ter) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R362R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GATA2 ENST00000341105.7 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.64

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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 49 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-128481878-G-A is Pathogenic according to our data. Variant chr3-128481878-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA2	NM_001145661.2	c.1084C>T	p.Arg362Ter	stop_gained	6/7	ENST00000487848.6	NP_001139133.1
GATA2	NM_032638.5	c.1084C>T	p.Arg362Ter	stop_gained	5/6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145662.1	c.1042C>T	p.Arg348Ter	stop_gained	5/6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.1084C>T	p.Arg362Ter	stop_gained	5/6	1	NM_032638.5	ENSP00000345681	P1
GATA2	ENST00000487848.6	c.1084C>T	p.Arg362Ter	stop_gained	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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2023	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Zhang 2015, Lovell 2016, Bluteau 2018, Donadieu 2018, Polat 2018, McReynolds 2019); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 27266944, 34670919, 32098966, 29146883, 25239263, 30578959, 29724903, 28440875, 30101490, 31753093, 30894283, 33363905, 28104920, 35753512, 34529785) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 03, 2023	PP1, PM2_supporting, PM6, PS4_moderate, PVS1 -

Deafness-lymphedema-leukemia syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Feb 02, 2024	- -

Leukemia, acute myeloid, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 24, 2015

- -

GATA2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The GATA2 c.1084C>T variant is predicted to result in premature protein termination (p.Arg362*). This variant has been reported in a number of patients with GATA2-related disorders (see for example Donadieu et al. 2018. PubMed ID: 29724903; Bluteau et al. 2018. PubMed ID: 29146883). This variant is not present in a large population database (https://gnomad.broadinstitute.org/) and has been interpreted as Pathogenic/Likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/435281/). 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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2023

This sequence change creates a premature translational stop signal (p.Arg362*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of GATA2-related conditions (PMID: 27266944, 29146883, 29724903, 32098966). ClinVar contains an entry for this variant (Variation ID: 435281). For these reasons, this variant has been classified as Pathogenic. -

GATA2 deficiency with susceptibility to MDS/AML Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Feb 24, 2024

The GATA2 c.1084C>T (p.Arg362Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. Loss-of-function variants in GATA2 are known to be pathogenic (PMID: 21670465, 23223431). This variant has been identified in multiple individuals with GATA2 deficiency (PMID: 25239263, 26702063, 26748574, 28440875, 29724903, 30894283, 32098966, 33363905, 34529785, 35273927, internal data). The variant was found to segregate with disease in multiple affected individuals in at least one family (PMID: 26748574, internal data). This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as 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

PVS1, PS4, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.97
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs1553770510; hg19: chr3-128200721; COSMIC: COSV62005735; COSMIC: COSV62005735;