chr3-128480819-G-A

Variant names:

• chr3-128480819-G-A
• rs10934857
• NM_032638.5:c.*200C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032638.5(GATA2):​c.*200C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 582,460 control chromosomes in the GnomAD database, including 16,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4035 hom., cov: 33)
  • Exomes 𝑓: 0.23 (12242 hom.)
• Consequence: GATA2 NM_032638.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.342
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-128480819-G-A is Benign according to our data. Variant chr3-128480819-G-A is described in ClinVar as Benign. ClinVar VariationId is 343127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_032638.5	c.*200C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145661.2	c.*200C>T		3_prime_UTR_variant	Exon 7 of 7		NP_001139133.1
GATA2	NM_001145662.1	c.*200C>T		3_prime_UTR_variant	Exon 6 of 6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.*200C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_032638.5	ENSP00000345681.2

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34115 AN: 152064 Hom.: 4031 Cov.: 33

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.241

GnomAD4 exome AF: 0.230 AC: 98915 AN: 430278 Hom.: 12242 Cov.: 5 AF XY: 0.225 AC XY: 49843 AN XY: 221842

African (AFR) AF: 0.190 AC: 2338 AN: 12328

American (AMR) AF: 0.238 AC: 3613 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 2871 AN: 12968

East Asian (EAS) AF: 0.131 AC: 3881 AN: 29668

South Asian (SAS) AF: 0.109 AC: 3397 AN: 31146

European-Finnish (FIN) AF: 0.222 AC: 7015 AN: 31660

Middle Eastern (MID) AF: 0.273 AC: 522 AN: 1914

European-Non Finnish (NFE) AF: 0.256 AC: 69250 AN: 270408

Other (OTH) AF: 0.241 AC: 6028 AN: 24978

GnomAD4 genome AF: 0.224 AC: 34132 AN: 152182 Hom.: 4035 Cov.: 33 AF XY: 0.221 AC XY: 16435 AN XY: 74390

African (AFR) AF: 0.192 AC: 7950 AN: 41514

American (AMR) AF: 0.232 AC: 3548 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 747 AN: 3472

East Asian (EAS) AF: 0.136 AC: 701 AN: 5170

South Asian (SAS) AF: 0.105 AC: 507 AN: 4826

European-Finnish (FIN) AF: 0.222 AC: 2346 AN: 10588

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17483 AN: 68000

Other (OTH) AF: 0.239 AC: 504 AN: 2112

Alfa AF: 0.248 Hom.: 2471

Bravo AF: 0.228

Asia WGS AF: 0.133 AC: 466 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

- -

Deafness-lymphedema-leukemia syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.53
DANN	Benign	0.59
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs10934857; hg19: chr3-128199662;