rs1553770949

chr3-128485944-C-CGTCAG

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.653_654insCTGAC(p.Glu219Ter) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T218T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA2 NM_032638.5 stop_gained, frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.56

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 3-128485944-C-CGTCAG is Pathogenic according to our data. Variant chr3-128485944-C-CGTCAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 539711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA2	NM_001145661.2	c.653_654insCTGAC	p.Glu219Ter	stop_gained, frameshift_variant	4/7	ENST00000487848.6
GATA2	NM_032638.5	c.653_654insCTGAC	p.Glu219Ter	stop_gained, frameshift_variant	3/6	ENST00000341105.7
GATA2	NM_001145662.1	c.653_654insCTGAC	p.Glu219Ter	stop_gained, frameshift_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA2	ENST00000341105.7	c.653_654insCTGAC	p.Glu219Ter	stop_gained, frameshift_variant	3/6	1	NM_032638.5	P1
GATA2	ENST00000487848.6	c.653_654insCTGAC	p.Glu219Ter	stop_gained, frameshift_variant	4/7	1	NM_001145661.2	P1
GATA2	ENST00000430265.6	c.653_654insCTGAC	p.Glu219Ter	stop_gained, frameshift_variant	3/6	1
GATA2	ENST00000696466.1	c.935_936insCTGAC	p.Glu313Ter	stop_gained, frameshift_variant	5/8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GATA2 are known to be pathogenic (PMID: 21670465, 23223431). This variant has not been reported in the literature in individuals with GATA2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu219*) in the GATA2 gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553770949; hg19: chr3-128204787;