3-128481937-GCGGC-GCGGCCGGC

Variant names:

• chr3-128481937-G-GCGGC
• rs869320770
• NM_032638.5:c.1021_1024dupGCCG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_032638.5(GATA2):​c.1021_1024dupGCCG​(p.Ala342GlyfsTer43) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A342A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GATA2 NM_032638.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.93
• Publications: 5 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: Pathogenic. The variant received 11 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 3-128481937-G-GCGGC is Pathogenic according to our data. Variant chr3-128481937-G-GCGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225277.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_032638.5	c.1021_1024dupGCCG	p.Ala342GlyfsTer43	frameshift_variant	Exon 5 of 6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145661.2	c.1021_1024dupGCCG	p.Ala342GlyfsTer43	frameshift_variant	Exon 6 of 7		NP_001139133.1
GATA2	NM_001145662.1	c.1018-39_1018-36dupGCCG		intron_variant	Intron 4 of 5		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.1021_1024dupGCCG	p.Ala342GlyfsTer43	frameshift_variant	Exon 5 of 6	1	NM_032638.5	ENSP00000345681.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Monocytopenia with susceptibility to infections Pathogenic:1 Uncertain:1

Jun 29, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift variant c.1021_1024dup(p.Ala342GlyfsTer43) has been submitted to ClinVar as a Likely Pathogenic, but no details are available for independent assessment. The p.Ala342GlyfsTer43 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant causes a frameshift starting with codon Alanine 342, changes this amino acid to Glycine residue, and creates a premature Stop codon at position 43 of the new reading frame, denoted p.Ala342GlyfsTer43. Loss of function variants have been previously reported to be disease causing. However, this variant is present in the penultimate exon, functional studies will be required to prove protein truncation. Hence the variant is classified as Uncertain Significance (VUS). -

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

Jun 04, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a premature translational stop signal in the GATA2 gene (p.Ala342Glyfs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 139 amino acids of the GATA2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with NK-cell deficiency (PMID: 23365458). This variant is also known as c.1025_1026insGCCG in the literature. ClinVar contains an entry for this variant (Variation ID: 225277). Variants that disrupt the p.Arg396 amino acid residue in GATA2 have been observed in affected individuals (PMID: 21670465, 22430350, 22533337, 23223431, 24077845, 25624456). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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. -

not provided Pathogenic:1

Feb 15, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 139 amino acid(s) are replaced with 42 different amino acid(s), and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34469508, 34893945, 23365458, 1714909, 28179282) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
BranchPoint Hunter		3.0
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs869320770; hg19: chr3-128200780;