17-44374449-C-T

Position:

chr17-44374449-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BS1BP2BP4

This summary comes from the ClinGen Evidence Repository: The ITGA2B missense variant c.2965G>A (p.Ala989Thr) has been observed in at least two probands with GT (PMIDs: 25539746, 15099289) however it was in cis with the pathogenic variant Val982Met.Expression in COS-7 cells did not reduce αIIbβ3 surface expression, however functionality was not assessed. Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.13. In summary, this variant meets criteria to be classified as Likely Benign for GT. GT-specific criteria applied: BP2 and BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8602498/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 3 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:4

Conservation

PhyloP100: 1.79

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 Likely_benign. Variant got -6 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.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ITGA2B	NM_000419.5 linkuse as main transcript	c.2965G>A	p.Ala989Thr	missense_variant	29/30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2 linkuse as main transcript	c.3016G>A	p.Ala1006Thr	missense_variant	28/29		XP_011523051.2
ITGA2B	XM_011524750.2 linkuse as main transcript	c.3096+210G>A		intron_variant			XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6 linkuse as main transcript	c.2965G>A	p.Ala989Thr	missense_variant	29/30	1	NM_000419.5	ENSP00000262407	P1	P08514-1
ITGA2B	ENST00000587295.5 linkuse as main transcript	c.253+1384G>A		intron_variant		3		ENSP00000467269
ITGA2B	ENST00000648408.1 linkuse as main transcript	c.2374+210G>A		intron_variant				ENSP00000498119
ITGA2B	ENST00000592462.5 linkuse as main transcript	n.2664G>A		non_coding_transcript_exon_variant	15/15	5

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000597

AC:

150

AN:

251386

Hom.:

AF XY:

0.000611

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000686

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000460

AC:

672

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

346

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000387

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152284

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000601

Hom.:

Bravo

AF:

0.000903

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000651

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00130

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 989 of the ITGA2B protein (p.Ala989Thr). This variant is present in population databases (rs78165611, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Glanzmann thrombasthenia who also carried additional ITGA2B variants that may account for their clinical status (PMID: 15099289, 20020534, 25539746). ClinVar contains an entry for this variant (Variation ID: 417951). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITGA2B protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect ITGA2B function (PMID: 15099289). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Jun 16, 2020	The ITGA2B missense variant c.2965G>A (p.Ala989Thr) has been observed in at least two probands with GT (PMIDs: 25539746, 15099289) however it was in cis with the pathogenic variant Val982Met.Expression in COS-7 cells did not reduce Î±IIbÎ²3 surface expression, however functionality was not assessed. Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.13. In summary, this variant meets criteria to be classified as Likely Benign for GT. GT-specific criteria applied: BP2 and BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	ITGA2B: BP4 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Glanzmann thrombasthenia;C5442010:Platelet-type bleeding disorder 16

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Feb 15, 2016

- -

ITGA2B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.044

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.76

M_CAP

Benign

0.035

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.6e-9

A;A

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

REVEL

Benign

0.13

Sift

Uncertain

0.017

Sift4G

Benign

0.22

Polyphen

0.017

Vest4

0.086

MVP

0.59

MPC

0.28

ClinPred

0.043

GERP RS

5.0

Varity_R

0.31

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -28

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