3-128481845-A-G

Position:

• chr3-128481845-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000341105.7(GATA2):​c.1117T>C​(p.Cys373Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C373Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GATA2 ENST00000341105.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.24

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.

• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-128481844-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1184165.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 3-128481845-A-G is Pathogenic according to our data. Variant chr3-128481845-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-128481845-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA2	NM_001145661.2	c.1117T>C	p.Cys373Arg	missense_variant	6/7	ENST00000487848.6	NP_001139133.1
GATA2	NM_032638.5	c.1117T>C	p.Cys373Arg	missense_variant	5/6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145662.1	c.1075T>C	p.Cys359Arg	missense_variant	5/6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.1117T>C	p.Cys373Arg	missense_variant	5/6	1	NM_032638.5	ENSP00000345681	P1
GATA2	ENST00000487848.6	c.1117T>C	p.Cys373Arg	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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 02, 2021	GATA2 c.1117T>C has been previously reported in a patient with Emberger syndrome. This GATA2 variant is absent from a large population dataset but has been reported in ClinVar (Variation ID:29720 ). p.Cys373Arg is predicted to alter one of the invariant zinc-coordinating cysteine residues in the second C4 zinc-finger domain of GATA2. In vitro functional studies indicate that p.Cys373Arg impacts the function of GATA2 by altering its interaction with the hematopoietic differentiation factor PU.1 and reducing its transactivation activity and DNA binding affinity. We consider GATA2 c.1117T>C to be likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21892158, 1714909, 28179282, 21956389, 26214525, 37580379, 28642594, 34387894, 31785092, 33038986, 29906059, 22147895, 35753998, 20803646) -

Deafness-lymphedema-leukemia syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 2011

- -

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

Likely pathogenic, criteria provided, single submitter

curation

Molecular Pathology Research Laboratory, SA Pathology

Jul 06, 2021

PS3_Supporting, PS4_Supporting, PM1, PM2, PM5, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.5	D
MutationAssessor	Pathogenic	5.1	H;.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.89		Gain of MoRF binding (P = 0.0068);.;Gain of MoRF binding (P = 0.0068);
MVP		0.99
MPC		4.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
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

LitVar

Other links and lift over

dbSNP: rs387906633; hg19: chr3-128200688;