rs1426175410

Variant names:

• chr3-128481881-G-A
• rs1426175410
• NM_032638.5:c.1081C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-128481881-G-A
• chr3-128481881-G-C

Variant summary

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

The NM_032638.5(GATA2):​c.1081C>T​(p.Arg361Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R361P) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.34

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 zinc_finger_region GATA-type 2 (size 24) in uniprot entity GATA2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_032638.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 3-128481881-G-A is Pathogenic according to our data. Variant chr3-128481881-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 472431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_032638.5	c.1081C>T	p.Arg361Cys	missense_variant	Exon 5 of 6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145661.2	c.1081C>T	p.Arg361Cys	missense_variant	Exon 6 of 7		NP_001139133.1
GATA2	NM_001145662.1	c.1039C>T	p.Arg347Cys	missense_variant	Exon 5 of 6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.1081C>T	p.Arg361Cys	missense_variant	Exon 5 of 6	1	NM_032638.5	ENSP00000345681.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jun 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 24266605, 21892158, 26812071, 24077845, 27418648, 30521493, 26702063, 31413257, 30933029, 31309983, 23502222, 24227816, 34469508, 35603181, 34529785, Bello2024[abstract], 24345756, 34387894, Abellard2023[abstract], 27013649, 1714909, 28179282, 25879889, 32135276) -

Apr 02, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monocytopenia with susceptibility to infections Pathogenic:1

Aug 03, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.97 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000472431 /PMID: 23502222 /3billion dataset). Different missense changes at the same codon (p.Arg361Gly, p.Arg361His, p.Arg361Leu, p.Arg361Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029721, VCV000435282, VCV001184156 /PMID: 21892158, 24077845, 29724903, 34529785). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 361 of the GATA2 protein (p.Arg361Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GATA2-related conditions (PMID: 23502222, 24077845, 24266605, 25879889, 26812071, 27418648, 32135276). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 472431). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GATA2 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg361 amino acid residue in GATA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21892158). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Acute myeloid leukemia;C3279664:Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections;C3463824:Myelodysplastic syndrome Pathogenic:1

Aug 23, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in at least 7 individuals with a range of clinical features including myelodysplastic syndrome, various types of cytopenia, recurrent infection, and lymphedema (Hsu 2013 PMID: 23502222; Webb 2016 PMID: 26812071; Gardner 2019 PMID: 30933029; Shamriz 2022 PMID: 35603181), including at least once as a de novo variant (Simon 2020 PMID: 32135276); additionally, this variant was found to segregate in at least 3 family members who were apparently asymptomatic but showed similarly reduced cell counts as their symptomatic family members (Svobodova 2013 PMID: 25879889; Nováková 2016 PMID: 27013649). This variant is present in 1 total allele in the Genome Aggregation Database (Highest reported MAF: 0.02% [1/5180]; https://gnomad.broadinstitute.org/variant/3-128481881-G-A?dataset=gnomad_r3); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, incomplete penetrance, and/or variable expressivity. This variant is also present in ClinVar, with classifications ranging from likely pathogenic to pathogenic (Variation ID: 472431). Evolutionary conservation and computational predictive tools strongly suggest that this variant may impact the protein. In summary, this variant is classified as pathogenic. -

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

Jul 06, 2021

Molecular Pathology Research Laboratory, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

PS4, PM1, PM5, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	5.1	H;.;H
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.96
MutPred		0.89		Loss of glycosylation at T357 (P = 0.0434);.;Loss of glycosylation at T357 (P = 0.0434);
MVP		0.99
MPC		3.6
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.99

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: rs1426175410; hg19: chr3-128200724; COSMIC: COSV100350976; COSMIC: COSV100350976;