rs5911

Variant names:

• chr17-44375697-A-C
• rs5911
• NM_000419.5:c.2621T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP2 BP4 BA1

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
• Clinical Significance: Benign reviewed by expert panel B:7 O:1
• Conservation: PhyloP100: 1.20
• Publications: 65 publications found

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 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 16

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Glanzmann thrombasthenia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Glanzmann's thrombasthenia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Glanzmann thrombasthenia 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA2B	NM_000419.5	c.2621T>G	p.Ile874Ser	missense_variant	Exon 26 of 30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.2774T>G	p.Ile925Ser	missense_variant	Exon 26 of 29		XP_011523051.2
ITGA2B	XM_011524750.2	c.2774T>G	p.Ile925Ser	missense_variant	Exon 26 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.2621T>G	p.Ile874Ser	missense_variant	Exon 26 of 30	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.2051T>G	p.Ile684Ser	missense_variant	Exon 22 of 25			ENSP00000498119.1
ITGA2B	ENST00000592462.5	n.1416T>G		non_coding_transcript_exon_variant	Exon 15 of 15	5
ITGA2B	ENST00000587295.5	c.252+136T>G		intron_variant	Intron 2 of 2	3		ENSP00000467269.1

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59117 AN: 151816 Hom.: 11571 Cov.: 32

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

GnomAD2 exomes AF: 0.390 AC: 80860 AN: 207394 AF XY: 0.386

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 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.: 44 AF XY: 0.377 AC XY: 268972 AN XY: 713728

African (AFR) AF: 0.375 AC: 12483 AN: 33278

American (AMR) AF: 0.372 AC: 14766 AN: 39732

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 10878 AN: 25560

East Asian (EAS) AF: 0.428 AC: 16648 AN: 38926

South Asian (SAS) AF: 0.346 AC: 28911 AN: 83490

European-Finnish (FIN) AF: 0.432 AC: 22209 AN: 51440

Middle Eastern (MID) AF: 0.353 AC: 2019 AN: 5724

European-Non Finnish (NFE) AF: 0.376 AC: 414121 AN: 1100854

Other (OTH) AF: 0.382 AC: 22759 AN: 59572

GnomAD4 genome AF: 0.389 AC: 59125 AN: 151934 Hom.: 11564 Cov.: 32 AF XY: 0.388 AC XY: 28837 AN XY: 74248

African (AFR) AF: 0.394 AC: 16334 AN: 41464

American (AMR) AF: 0.349 AC: 5332 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1515 AN: 3472

East Asian (EAS) AF: 0.445 AC: 2288 AN: 5138

South Asian (SAS) AF: 0.352 AC: 1694 AN: 4812

European-Finnish (FIN) AF: 0.435 AC: 4598 AN: 10566

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26136 AN: 67910

Other (OTH) AF: 0.359 AC: 756 AN: 2106

Alfa AF: 0.381 Hom.: 6522

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:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2020

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Mar 06, 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. -

not specified Benign:2

Sep 08, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glanzmann thrombasthenia 1 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BAK PLATELET-SPECIFIC ANTIGEN Other:1

Apr 13, 2021

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.1	N
PhyloP100		1.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.055
Sift	Benign	0.21	T
Sift4G	Benign	0.32	T
Polyphen		0.0010	B
Vest4		0.032
MPC		0.42
ClinPred		0.0069	T
GERP RS		3.4
PromoterAI		0.012	Neutral
Varity_R		0.049
gMVP		0.32
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: rs5911; hg19: chr17-42453065; COSMIC: COSV52233480; COSMIC: COSV52233480;