17-44372408-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.5:c.3076C>T variant results in the Arg1026Trp missense change. It is absent in population databases and is predicted damaging by in silico tools (REVEL score of 0.897). All the individuals with this variant, reported in the literature, are heterozygous and have macrothrombocytopenia with or without a mild bleeding tendency (PMID:31119735, 21454453, 31064749). In summary, there is insufficient evidence at this time to classify the Arg1026Trp variant. GT-specific criteria applied: PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10575573/MONDO:0010119/011

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

11
7
1

Clinical Significance

Uncertain significance reviewed by expert panel P:13U:1

Conservation

PhyloP100: 1.67
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
PP3

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ITGA2BNM_000419.5 linkuse as main transcriptc.3076C>T p.Arg1026Trp missense_variant 30/30 ENST00000262407.6
ITGA2BXM_011524749.2 linkuse as main transcriptc.3127C>T p.Arg1043Trp missense_variant 29/29
ITGA2BXM_011524750.2 linkuse as main transcriptc.3112C>T p.Arg1038Trp missense_variant 29/29

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ITGA2BENST00000262407.6 linkuse as main transcriptc.3076C>T p.Arg1026Trp missense_variant 30/301 NM_000419.5 P1P08514-1
ITGA2BENST00000648408.1 linkuse as main transcriptc.2392C>T p.Arg798Trp missense_variant 25/25
ITGA2BENST00000587295.5 linkuse as main transcriptc.271C>T p.Arg91Trp missense_variant 3/33

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461852
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:13Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Platelet-type bleeding disorder 16 Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingWangler Lab, Baylor College of Medicine-This missense ITGA2B variant at c.3076C>T (p.R1026W) was discovered on exome through the Texome Project (R01HG011795). It is reported in the heterozygous state in individuals with ITGA2B-related disorders including autosomal dominant macrothrombocytopenia and autosomal dominant thrombocytopenia with normal platelet size (PMID: 21454453, 29090484, 31064749, 31119735, 32581362). Functional studies suggest this variant is functionally defective (PMID: 21454453, 31691484) (PS3). This variant has not been observed in gnomAD (PM2) and is predicted to be deleterious by multiple computational models (CADD:25.200) (PP3). The evolutionary conservation of this residue is high. We classify this variant as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 28, 2022- -
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityFeb 05, 2020- -
Likely pathogenic, criteria provided, single submitterclinical testingISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 19, 2011- -
Glanzmann thrombasthenia Pathogenic:2Uncertain:1
Uncertain significance, reviewed by expert panelcurationClinGen Platelet Disorders Variant Curation Expert Panel, ClinGenJun 16, 2020The NM_000419.5:c.3076C>T variant results in the Arg1026Trp missense change. It is absent in population databases and is predicted damaging by in silico tools (REVEL score of 0.897). All the individuals with this variant, reported in the literature, are heterozygous and have macrothrombocytopenia with or without a mild bleeding tendency (PMID: 31119735, 21454453, 31064749). In summary, there is insufficient evidence at this time to classify the Arg1026Trp variant. GT-specific criteria applied: PM2_Supporting, PP3. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2023This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1026 of the ITGA2B protein (p.Arg1026Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant thrombocytopenia (PMID: 21454453, 29090484, 31119735). It has also been observed to segregate with disease in related individuals. This variant is also known as p.R995W. ClinVar contains an entry for this variant (Variation ID: 50233). 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 expected to disrupt ITGA2B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ITGA2B function (PMID: 21454453). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsNov 23, 2018This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals [PMID 21454453, 29090484] -
Thrombocytopenia Pathogenic:2
Pathogenic, criteria provided, single submitterresearchNIHR Bioresource Rare Diseases, University of CambridgeFeb 01, 2019- -
Pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeSep 01, 2019The clinical significance is unchnaged from the previous submission. -
ITGA2B-related disorder Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 17, 2024The ITGA2B c.3076C>T variant is predicted to result in the amino acid substitution p.Arg1026Trp. This variant (aka R995W) has been reported in several unrelated families to be a cause of autosomal dominant macrothrombocytopenia (Kunishima et al. 2011. PubMed ID: 21454453; Khoriaty et al. 2019. PubMed ID: 31119735). Functional studies show that the p.Arg1026Trp variant causes defective platelet activation (Kunishima et al. 2011. PubMed ID: 21454453). A similar variant, p.Arg1026Gln, has also reported in an individual with Glanzmann thrombasthenia (French et al. 1997. PubMed ID: 9215749) suggesting that amino acid residue p.Arg1026 is important for proper ITGA2B function. This variant has not been reported in a large population database, indicating this variant is rare. In summary, the c.3076C>T variant is categorized as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 15, 2024Variant summary: ITGA2B c.3076C>T (p.Arg1026Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251260 control chromosomes. c.3076C>T has been reported in the literature in multiple individuals affected with macrothrombocytopenia (Kunishima_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that the variant leads to constitutive activation, membrane ruffling, abnormal cytoplasmic protrusions, and defective proplatelet formation (Kunishima_2011). In addition, knock-in mice with this variant developed macrothrombocytopenia, which was primarily attributed to impaired proplatelet formation (Akuta_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31691484, 21454453). In ClinVar contains an entry for this variant (Variation ID: 50233). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 15, 2017- -
Glanzmann thrombasthenia 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 28, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Pathogenic
4.0
H
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-6.5
D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.89
Loss of disorder (P = 0.0082);
MVP
0.89
MPC
1.0
ClinPred
1.0
D
GERP RS
2.4
Varity_R
0.90
gMVP
0.86

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.

Other links and lift over

dbSNP: rs766503255; hg19: chr17-42449776; COSMIC: COSV52231603; COSMIC: COSV52231603; API