rs5911

Positions:

chr17-44375697-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP2BP4BA1

This summary comes from the ClinGen Evidence Repository: The ITGA2B c.2621T>G (p.Ile874Ser) missense variant has been reported many times in the literature as an alloantigenic site. This variant has been observed in cis with several other Glanzmann thrombasthenia variants, including the pathogenic Tyr471Ter and c.1440-13_1440-1del ITGA2B variants and the Pro189Ser ITGB3 variant (PMID:25728920). It is present in gnomAD at an overall allele frequency of 0.39177 (and 0.43954 in the non-Finnish European population). Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.055. In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1, BP2, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115831/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.39 ( 11564 hom., cov: 32)

Exomes 𝑓: 0.38 ( 103365 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:6O:1

Conservation

PhyloP100: 1.20

Variant links:

Genes affected

ITGA2B (HGNC:6138): (integrin subunit alpha 2b) This gene encodes a member of the integrin alpha chain family of proteins. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate through disulfide linkages to form a subunit of the alpha-IIb/beta-3 integrin cell adhesion receptor. This receptor plays a crucial role in the blood coagulation system, by mediating platelet aggregation. Mutations in this gene are associated with platelet-type bleeding disorders, which are characterized by a failure of platelet aggregation, including Glanzmann thrombasthenia. [provided by RefSeq, Jan 2016]

ITGA2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP2

BP4

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ITGA2B	NM_000419.5 linkuse as main transcript	c.2621T>G	p.Ile874Ser	missense_variant	26/30	ENST00000262407.6
ITGA2B	XM_011524749.2 linkuse as main transcript	c.2774T>G	p.Ile925Ser	missense_variant	26/29
ITGA2B	XM_011524750.2 linkuse as main transcript	c.2774T>G	p.Ile925Ser	missense_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6 linkuse as main transcript	c.2621T>G	p.Ile874Ser	missense_variant	26/30	1	NM_000419.5	P1	P08514-1
ITGA2B	ENST00000648408.1 linkuse as main transcript	c.2054T>G	p.Ile685Ser	missense_variant	22/25
ITGA2B	ENST00000587295.5 linkuse as main transcript	c.253+136T>G		intron_variant		3
ITGA2B	ENST00000592462.5 linkuse as main transcript	n.1416T>G		non_coding_transcript_exon_variant	15/15	5

Frequencies

GnomAD3 genomes

AF:

0.389

AC:

59117

AN:

151816

Hom.:

11571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.394

Gnomad AMI

AF:

0.413

Gnomad AMR

AF:

0.349

Gnomad ASJ

AF:

0.436

Gnomad EAS

AF:

0.446

Gnomad SAS

AF:

0.354

Gnomad FIN

AF:

0.435

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.385

Gnomad OTH

AF:

0.362

GnomAD3 exomes

AF:

0.390

AC:

80860

AN:

207394

Hom.:

15584

AF XY:

0.386

AC XY:

43277

AN XY:

112254

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.379

Gnomad ASJ exome

AF:

0.424

Gnomad EAS exome

AF:

0.432

Gnomad SAS exome

AF:

0.345

Gnomad FIN exome

AF:

0.441

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.367

GnomAD4 exome

AF:

0.379

AC:

544794

AN:

1438576

Hom.:

103365

Cov.:

AF XY:

0.377

AC XY:

268972

AN XY:

713728

show subpopulations

Gnomad4 AFR exome

AF:

0.375

Gnomad4 AMR exome

AF:

0.372

Gnomad4 ASJ exome

AF:

0.426

Gnomad4 EAS exome

AF:

0.428

Gnomad4 SAS exome

AF:

0.346

Gnomad4 FIN exome

AF:

0.432

Gnomad4 NFE exome

AF:

0.376

Gnomad4 OTH exome

AF:

0.382

GnomAD4 genome

AF:

0.389

AC:

59125

AN:

151934

Hom.:

11564

Cov.:

AF XY:

0.388

AC XY:

28837

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.394

Gnomad4 AMR

AF:

0.349

Gnomad4 ASJ

AF:

0.436

Gnomad4 EAS

AF:

0.445

Gnomad4 SAS

AF:

0.352

Gnomad4 FIN

AF:

0.435

Gnomad4 NFE

AF:

0.385

Gnomad4 OTH

AF:

0.359

Alfa

AF:

0.382

Hom.:

6204

Bravo

AF:

0.382

TwinsUK

AF:

0.370

AC:

1372

ALSPAC

AF:

0.363

AC:

1399

ESP6500AA

AF:

0.390

AC:

1714

ESP6500EA

AF:

0.374

AC:

3211

ExAC

AF:

0.359

AC:

42729

Asia WGS

AF:

0.402

AC:

1404

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Benign:3

Benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Nov 10, 2020	The ITGA2B c.2621T>G (p.Ile874Ser) missense variant has been reported many times in the literature as an alloantigenic site. This variant has been observed in cis with several other Glanzmann thrombasthenia variants, including the pathogenic Tyr471Ter and c.1440-13_1440-1del ITGA2B variants and the Pro189Ser ITGB3 variant (PMID: 25728920). It is present in gnomAD at an overall allele frequency of 0.39177 (and 0.43954 in the non-Finnish European population). Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.055. In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1, BP2, BP4. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Glanzmann thrombasthenia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

BAK PLATELET-SPECIFIC ANTIGEN

Other:1

association, no assertion criteria provided

literature only

OMIM

Apr 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.041

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.1

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

2.0

REVEL

Benign

0.055

Sift

Benign

0.21

Sift4G

Benign

0.32

Polyphen

0.0010

Vest4

0.032

MPC

0.42

ClinPred

0.0069

GERP RS

3.4

Varity_R

0.049

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over