3-128486034-C-G

Variant names:

• chr3-128486034-C-G
• rs34870876
• NM_032638.5:c.564G>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032638.5(GATA2):​c.564G>C​(p.Thr188Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,605,602 control chromosomes in the GnomAD database, including 2,720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (179 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2541 hom.)
• Consequence: GATA2 NM_032638.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.77

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-128486034-C-G is Benign according to our data. Variant chr3-128486034-C-G is described in ClinVar as [Benign]. Clinvar id is 257566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-128486034-C-G is described in Lovd as [Benign]. Variant chr3-128486034-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_032638.5	c.564G>C	p.Thr188Thr	synonymous_variant	Exon 3 of 6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145661.2	c.564G>C	p.Thr188Thr	synonymous_variant	Exon 4 of 7		NP_001139133.1
GATA2	NM_001145662.1	c.564G>C	p.Thr188Thr	synonymous_variant	Exon 3 of 6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.564G>C	p.Thr188Thr	synonymous_variant	Exon 3 of 6	1	NM_032638.5	ENSP00000345681.2

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6013 AN: 151698 Hom.: 179 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0796

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.00811

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.0918

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0588

Gnomad OTH AF: 0.0355

GnomAD3 exomes AF: 0.0408 AC: 10218 AN: 250610 Hom.: 320 AF XY: 0.0413 AC XY: 5599 AN XY: 135692

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0240

Gnomad FIN exome AF: 0.0881

Gnomad NFE exome AF: 0.0582

Gnomad OTH exome AF: 0.0388

GnomAD4 exome AF: 0.0541 AC: 78645 AN: 1453782 Hom.: 2541 Cov.: 34 AF XY: 0.0529 AC XY: 38285 AN XY: 723156

Gnomad4 AFR exome AF: 0.00791

Gnomad4 AMR exome AF: 0.0150

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.0237

Gnomad4 FIN exome AF: 0.0911

Gnomad4 NFE exome AF: 0.0614

Gnomad4 OTH exome AF: 0.0443

GnomAD4 genome AF: 0.0396 AC: 6012 AN: 151820 Hom.: 179 Cov.: 32 AF XY: 0.0401 AC XY: 2977 AN XY: 74224

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.00811

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.0217

Gnomad4 FIN AF: 0.0918

Gnomad4 NFE AF: 0.0588

Gnomad4 OTH AF: 0.0351

Alfa AF: 0.0370 Hom.: 63

Bravo AF: 0.0327

Asia WGS AF: 0.00924 AC: 33 AN: 3478

EpiCase AF: 0.0481

EpiControl AF: 0.0482

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 13, 2017

PreventionGenetics, part of Exact Sciences

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

- -

-

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

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

- -

not provided Benign:4

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Nov 21, 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

- -

Deafness-lymphedema-leukemia syndrome Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.022
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs34870876; hg19: chr3-128204877;