rs148554346

chr3-128486265-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032638.5(GATA2):c.333C>T(p.His111=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,571,482 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (4 hom.)
• Consequence: GATA2 NM_032638.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.38

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=-0.66).
• BP6: Variant 3-128486265-G-A is Benign according to our data. Variant chr3-128486265-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0021 (319/152258) while in subpopulation AFR AF= 0.00729 (303/41554). AF 95% confidence interval is 0.00662. There are 0 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 314 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA2	NM_001145661.2	c.333C>T	p.His111=	synonymous_variant	4/7	ENST00000487848.6
GATA2	NM_032638.5	c.333C>T	p.His111=	synonymous_variant	3/6	ENST00000341105.7
GATA2	NM_001145662.1	c.333C>T	p.His111=	synonymous_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA2	ENST00000341105.7	c.333C>T	p.His111=	synonymous_variant	3/6	1	NM_032638.5	P1
GATA2	ENST00000487848.6	c.333C>T	p.His111=	synonymous_variant	4/7	1	NM_001145661.2	P1

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000495 AC: 87 AN: 175898 Hom.: 0 AF XY: 0.000391 AC XY: 37 AN XY: 94552

Gnomad AFR exome AF: 0.00783

Gnomad AMR exome AF: 0.000195

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000715

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000424

GnomAD4 exome AF: 0.000205 AC: 291 AN: 1419224 Hom.: 4 Cov.: 36 AF XY: 0.000164 AC XY: 115 AN XY: 701498

Gnomad4 AFR exome AF: 0.00717

Gnomad4 AMR exome AF: 0.000272

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000713

GnomAD4 genome AF: 0.00210 AC: 319 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74438

Gnomad4 AFR AF: 0.00729

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00235

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 22, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Deafness-lymphedema-leukemia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 12, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	5.6
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs148554346; hg19: chr3-128205108; COSMIC: COSV62003898; COSMIC: COSV62003898;