17-44372385-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The missense variant c.3099A>T (p.Glu1033Asp) has been reported heterozygous in one patient (PMID:31064749) however a second variant was not identified. Communication with the authors confirmed the patient had decreased platelet glycoprotein IIb-IIIa, abnormal bleeding, and impaired platelet aggregation with ADP, epinephrine, arachidonic acid, and collagen. The highest population minor allele frequency in gnomAD v4.0.0 is 0.00003334 (2/59980 alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). Computational predictors agree that this variant does not have a deleterious effect (REVEL score of 0.193; BP4). In summary, this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PM2_supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA290942825/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

19

Clinical Significance

Uncertain significance reviewed by expert panel U:3

Conservation

PhyloP100: 0.0330
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 0 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
BP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITGA2BNM_000419.5 linkc.3099A>T p.Glu1033Asp missense_variant Exon 30 of 30 ENST00000262407.6 NP_000410.2 P08514-1
ITGA2BXM_011524749.2 linkc.3150A>T p.Glu1050Asp missense_variant Exon 29 of 29 XP_011523051.2 P08514
ITGA2BXM_011524750.2 linkc.3135A>T p.Glu1045Asp missense_variant Exon 29 of 29 XP_011523052.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITGA2BENST00000262407.6 linkc.3099A>T p.Glu1033Asp missense_variant Exon 30 of 30 1 NM_000419.5 ENSP00000262407.5 P08514-1
ITGA2BENST00000648408.1 linkc.2412A>T p.Glu804Asp missense_variant Exon 25 of 25 ENSP00000498119.1 A0A3B3IU79
ITGA2BENST00000587295.5 linkc.291A>T p.Glu97Asp missense_variant Exon 3 of 3 3 ENSP00000467269.1 K7EP83

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152074
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461870
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
10
AN XY:
727238
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:
0.0000108
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152074
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Glanzmann thrombasthenia Uncertain:2
Uncertain significance, reviewed by expert panelcurationClinGen Platelet Disorders Variant Curation Expert Panel, ClinGenMay 02, 2024The missense variant c.3099A>T (p.Glu1033Asp) has been reported heterozygous in one patient (PMID: 31064749) however a second variant was not identified. Communication with the authors confirmed the patient had decreased platelet glycoprotein IIb-IIIa, abnormal bleeding, and impaired platelet aggregation with ADP, epinephrine, arachidonic acid, and collagen. The highest population minor allele frequency in gnomAD v4.0.0 is 0.00003334 (2/59980 alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). Computational predictors agree that this variant does not have a deleterious effect (REVEL score of 0.193; BP4). In summary, this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PM2_supporting, BP4. -
Uncertain significance, criteria provided, single submitterresearchNIHR Bioresource Rare Diseases, University of CambridgeFeb 01, 2019- -
ITGA2B-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 09, 2023The ITGA2B c.3099A>T variant is predicted to result in the amino acid substitution p.Glu1033Asp. This variant was reported in an individual with platelet function disorder (Supplementary File 3 in Downes et al. 2019. PubMed ID: 31064749). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is reported as a variant of uncertain significance in ClinVar by the ClinGen Platelet Disorders Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/627299/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.080
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
9.4
DANN
Benign
0.87
DEOGEN2
Benign
0.27
T
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.60
D
LIST_S2
Benign
0.39
T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.058
T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
1.6
L
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.070
N
REVEL
Benign
0.19
Sift
Benign
1.0
T
Sift4G
Benign
0.75
T
Polyphen
0.0060
B
Vest4
0.13
MutPred
0.42
Gain of loop (P = 0.0166);
MVP
0.46
MPC
0.27
ClinPred
0.062
T
GERP RS
-1.5
Varity_R
0.044
gMVP
0.37

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: rs757116551; hg19: chr17-42449753; API