chr17-44372407-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The NM_000419.5:c.3077G>A variant results in the Arg1026Gln missense change. It is absent in population databases, including gnomADv2.1.1 (PM2_supporting), and is predicted damaging by in silico tools (REVEL score of 0.904; PP3). One compound heterozygous individual with mild bleeding, thrombocytopenia and platelet anisotrpy is reported in the literature several times (PMID:25728920) with confirmation of c.1440-13_1440-1del (classified Pathogenic by the PD VCEP; PM3) in trans. The variant results in reduced expression of the αIIbβ3 complex on platelet surface. The expressed αIIbβ3 was not constitutively active and were able to bind fibrinogen only upon activation by anti-LIBS antibody. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM3, PP3 (PD VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10575572/MONDO:0010119/011

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:3

Conservation

PhyloP100: 4.08

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

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

PM3

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

PP3

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 link	c.3077G>A	p.Arg1026Gln	missense_variant	Exon 30 of 30	ENST00000262407.6	NP_000410.2	P08514-1
ITGA2B	XM_011524749.2 link	c.3128G>A	p.Arg1043Gln	missense_variant	Exon 29 of 29		XP_011523051.2	P08514
ITGA2B	XM_011524750.2 link	c.3113G>A	p.Arg1038Gln	missense_variant	Exon 29 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITGA2B	ENST00000262407.6 link	c.3077G>A	p.Arg1026Gln	missense_variant	Exon 30 of 30	1	NM_000419.5	ENSP00000262407.5	P08514-1
ITGA2B	ENST00000648408.1 link	c.2390G>A	p.Arg797Gln	missense_variant	Exon 25 of 25			ENSP00000498119.1	A0A3B3IU79
ITGA2B	ENST00000587295.5 link	c.269G>A	p.Arg90Gln	missense_variant	Exon 3 of 3	3		ENSP00000467269.1	K7EP83

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251278

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Platelet-type bleeding disorder 16

Pathogenic:2

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Uncertain:1

Apr 07, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ITGA2B c.3077G>A (p.Arg1026Gln, also known as p.Arg995Gln in literatures) results in a conservative amino acid change located in the cytoplasmic domain (Peyruchaud_1998) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, multiple structural studies showed alphaIIb R995/beta D732 salt bridge confers stability on the inactive state of integrin, supporting this residue is important for protein function (Ghevaert_2007, Yang_2009, Jayo_2010). The variant allele was found at a frequency of 4e-06 in 251278 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3077G>A has been reported in the literature in individuals affected with Glanzmann Thrombasthenia-Like Syndrome (Nurden_2015, French_1997, Peyruchaud_1998, Morais_2020). These data do not allow any conclusion about variant significance. At least one functional study reports this variant decreases surface alphaIIb -beta3 expression by approximately 50% of WT in cells and the mutated complex was not in a high activation state but remained functional in that activation could be induced by the anti-LIBS6 antibody (Peyruchaud_1998). Two ClinVar submitters (evaluation after 2014), including one expert panel (ClinGen Platelet Disorders Variant Curation Expert Panel,ClinGen), cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Glanzmann thrombasthenia

Uncertain:1

Sep 07, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000419.5:c.3077G>A variant results in the Arg1026Gln missense change. It is absent in population databases, including gnomADv2.1.1 (PM2_supporting), and is predicted damaging by in silico tools (REVEL score of 0.904; PP3). One compound heterozygous individual with mild bleeding, thrombocytopenia and platelet anisotrpy is reported in the literature several times (PMID: 25728920) with confirmation of c.1440-13_1440-1del (classified Pathogenic by the PD VCEP; PM3) in trans. The variant results in reduced expression of the αIIbβ3 complex on platelet surface. The expressed αIIbβ3 was not constitutively active and were able to bind fibrinogen only upon activation by anti-LIBS antibody. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM3, PP3 (PD VCEP specifications version 2.1). -

Thrombocytopenia

Uncertain:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.4

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.96

Loss of MoRF binding (P = 0.0901);

MVP

0.92

MPC

1.1

ClinPred

1.0

GERP RS

4.5

Varity_R

0.96

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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