rs137852907

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3_SupportingPP3PM2_SupportingPS3_ModeratePP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.818G>A (p.Gly273Asp) variant has been reported, in the homozygous state (PM3_supporting), in at least one proband (PMID:8282784) with a GT-specific phenotype. The patient in PMID:8282784 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, the patient had <5% expression by flow cytometry. The variant is absent from gnomADv4.0 (PM2_supporting) and is predicted deleterious (REVEL score 0.845; PP3). Heterologous expression followed by the preferred assays, of either Western blot or flow cytometry, has not been reported for this variant. However in PMID:8282784, to test for mutant complexes on the cell surface, COS-1 cells were cotransfected with WT ITGB3 and Gly273Asp ITGA2B, cells were surface labeled with 125I and immunoprecipitated, then labeled heterodimers were detected on the surface of cotransfected cells containing wildtype ITGA2B but not on the surface of cells containing Gly273Asp. PMID:8916916 reports similar immunoprecipitation results. These results were considered sufficient evidence of impaired surface expression for application of the PS3_moderate criteria. In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PS3_moderate, PM2_supporting, PM3_supporting, PP3, and PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115837/MONDO:0010119/011

Frequency

Genomes: not found (cov: 32)

Consequence

ITGA2B
NM_000419.5 missense

Scores

11
6
2

Clinical Significance

Likely pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 2.69
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
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.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ITGA2BNM_000419.5 linkuse as main transcriptc.818G>A p.Gly273Asp missense_variant 8/30 ENST00000262407.6 NP_000410.2 P08514-1
ITGA2BXM_011524749.2 linkuse as main transcriptc.971G>A p.Gly324Asp missense_variant 8/29 XP_011523051.2 P08514
ITGA2BXM_011524750.2 linkuse as main transcriptc.971G>A p.Gly324Asp missense_variant 8/29 XP_011523052.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ITGA2BENST00000262407.6 linkuse as main transcriptc.818G>A p.Gly273Asp missense_variant 8/301 NM_000419.5 ENSP00000262407.5 P08514-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen Platelet Disorders Variant Curation Expert Panel, ClinGenMay 02, 2024The NM_000419.5(ITGA2B):c.818G>A (p.Gly273Asp) variant has been reported, in the homozygous state (PM3_supporting), in at least one proband (PMID: 8282784) with a GT-specific phenotype. The patient in PMID: 8282784 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, the patient had <5% expression by flow cytometry. The variant is absent from gnomADv4.0 (PM2_supporting) and is predicted deleterious (REVEL score 0.845; PP3). Heterologous expression followed by the preferred assays, of either Western blot or flow cytometry, has not been reported for this variant. However in PMID: 8282784, to test for mutant complexes on the cell surface, COS-1 cells were cotransfected with WT ITGB3 and Gly273Asp ITGA2B, cells were surface labeled with 125I and immunoprecipitated, then labeled heterodimers were detected on the surface of cotransfected cells containing wildtype ITGA2B but not on the surface of cells containing Gly273Asp. PMID: 8916916 reports similar immunoprecipitation results. These results were considered sufficient evidence of impaired surface expression for application of the PS3_moderate criteria. In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PS3_moderate, PM2_supporting, PM3_supporting, PP3, and PP4_moderate. -
Glanzmann thrombasthenia 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 1994- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.79
T
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Pathogenic
3.6
H
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-6.2
D
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0070
D
Polyphen
1.0
D
Vest4
0.97
MutPred
0.87
Gain of sheet (P = 0.0827);
MVP
0.91
MPC
2.3
ClinPred
0.99
D
GERP RS
4.9
Varity_R
0.92
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs137852907; hg19: chr17-42461935; API