3-128487017-G-C

Variant names:

• chr3-128487017-G-C
• rs1573858
• NM_001145661.2:c.15C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001145661.2(GATA2):​c.15C>G​(p.Pro5Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 1,589,600 control chromosomes in the GnomAD database, including 326,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P5P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.68 (35936 hom., cov: 35)
  • Exomes 𝑓: 0.63 (290735 hom.)
• Consequence: GATA2 NM_001145661.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: -5.44
• Publications: 39 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-128487017-G-C is Benign according to our data. Variant chr3-128487017-G-C is described in ClinVar as Benign. ClinVar VariationId is 257563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145661.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA2	NM_001145661.2	MANE Plus Clinical	c.15C>G	p.Pro5Pro	synonymous	Exon 3 of 7	NP_001139133.1
	GATA2	NM_032638.5	MANE Select	c.15C>G	p.Pro5Pro	synonymous	Exon 2 of 6	NP_116027.2
	GATA2	NM_001145662.1		c.15C>G	p.Pro5Pro	synonymous	Exon 2 of 6	NP_001139134.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA2	ENST00000341105.7	TSL:1 MANE Select	c.15C>G	p.Pro5Pro	synonymous	Exon 2 of 6	ENSP00000345681.2
	GATA2	ENST00000487848.6	TSL:1 MANE Plus Clinical	c.15C>G	p.Pro5Pro	synonymous	Exon 3 of 7	ENSP00000417074.1
	GATA2	ENST00000430265.6	TSL:1	c.15C>G	p.Pro5Pro	synonymous	Exon 2 of 6	ENSP00000400259.2

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103585 AN: 152070 Hom.: 35892 Cov.: 35

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.777

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.691

GnomAD2 exomes AF: 0.665 AC: 137413 AN: 206734 AF XY: 0.662

Gnomad AFR exome AF: 0.786

Gnomad AMR exome AF: 0.709

Gnomad ASJ exome AF: 0.752

Gnomad EAS exome AF: 0.709

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.638

Gnomad OTH exome AF: 0.678

GnomAD4 exome AF: 0.634 AC: 911208 AN: 1437412 Hom.: 290735 Cov.: 52 AF XY: 0.635 AC XY: 452850 AN XY: 712660

African (AFR) AF: 0.793 AC: 26226 AN: 33064

American (AMR) AF: 0.712 AC: 29505 AN: 41446

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 19172 AN: 25478

East Asian (EAS) AF: 0.641 AC: 24786 AN: 38652

South Asian (SAS) AF: 0.673 AC: 56100 AN: 83304

European-Finnish (FIN) AF: 0.538 AC: 27089 AN: 50392

Middle Eastern (MID) AF: 0.778 AC: 4418 AN: 5676

European-Non Finnish (NFE) AF: 0.622 AC: 684710 AN: 1100094

Other (OTH) AF: 0.661 AC: 39202 AN: 59306

GnomAD4 genome AF: 0.681 AC: 103686 AN: 152188 Hom.: 35936 Cov.: 35 AF XY: 0.677 AC XY: 50405 AN XY: 74412

African (AFR) AF: 0.786 AC: 32641 AN: 41544

American (AMR) AF: 0.718 AC: 10984 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 2543 AN: 3472

East Asian (EAS) AF: 0.702 AC: 3625 AN: 5162

South Asian (SAS) AF: 0.656 AC: 3166 AN: 4828

European-Finnish (FIN) AF: 0.531 AC: 5631 AN: 10606

Middle Eastern (MID) AF: 0.771 AC: 225 AN: 292

European-Non Finnish (NFE) AF: 0.628 AC: 42716 AN: 67970

Other (OTH) AF: 0.692 AC: 1461 AN: 2110

Alfa AF: 0.652 Hom.: 9943

Bravo AF: 0.702

Asia WGS AF: 0.671 AC: 2330 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Apr 04, 2018

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 88% of patients studied by a panel of primary immunodeficiencies. Number of patients: 84. Only high quality variants are reported.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 31, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3 Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.

Sep 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Deafness-lymphedema-leukemia syndrome Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Monocytopenia with susceptibility to infections Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Oct 18, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.4
DANN	Benign	0.85
PhyloP100		-5.4
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1573858; hg19: chr3-128205860; COSMIC: COSV62003056; COSMIC: COSV62003056;