17-44381058-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_ModeratePM2_SupportingPP4_StrongPM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.1214T>C (p.Ile405Thr) variant has been reported in at least four compound heterozygous probands (PMIDs: 12424194, 12083483, 24418945, 25728920) with a phenotype highly specific to GT. In one case the variant cosegregated with disease in the proband and two siblings (PMID:12424194). It is absent from Exac and gnomAD. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PM3_Strong, PM2_Supporting, PP1_Moderate, PP3 and PP4_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA290950815/MONDO:0010119/011

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

4
11
4

Clinical Significance

Pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 7.06
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 Pathogenic. Variant got 11 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.
PP1
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 rank MANE Protein UniProt
ITGA2BNM_000419.5 linkc.1214T>C p.Ile405Thr missense_variant Exon 13 of 30 ENST00000262407.6 NP_000410.2 P08514-1
ITGA2BXM_011524749.2 linkc.1367T>C p.Ile456Thr missense_variant Exon 13 of 29 XP_011523051.2 P08514
ITGA2BXM_011524750.2 linkc.1367T>C p.Ile456Thr missense_variant Exon 13 of 29 XP_011523052.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITGA2BENST00000262407.6 linkc.1214T>C p.Ile405Thr missense_variant Exon 13 of 30 1 NM_000419.5 ENSP00000262407.5 P08514-1
ITGA2BENST00000648408.1 linkc.644T>C p.Ile215Thr missense_variant Exon 9 of 25 ENSP00000498119.1 A0A3B3IU79
ITGA2BENST00000592226.5 linkn.454T>C non_coding_transcript_exon_variant Exon 7 of 10 5
ITGA2BENST00000592462.5 linkn.9T>C non_coding_transcript_exon_variant Exon 2 of 15 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461000
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
726730
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.:
32
Alfa
AF:
0.0000334
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1
Mar 05, 2021
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.1214T>C (p.Ile405Thr) variant has been reported in at least four compound heterozygous probands (PMIDs: 12424194, 12083483, 24418945, 25728920) with a phenotype highly specific to GT. In one case the variant cosegregated with disease in the proband and two siblings (PMID: 12424194). It is absent from Exac and gnomAD. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PM3_Strong, PM2_Supporting, PP1_Moderate, PP3 and PP4_Strong. -

Glanzmann thrombasthenia 1 Pathogenic:1
-
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.82
T
M_CAP
Benign
0.080
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.13
D
MutationAssessor
Uncertain
2.8
M
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-3.6
D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.87
P
Vest4
0.88
MutPred
0.95
Loss of stability (P = 0.0166);
MVP
0.91
MPC
0.49
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.73
gMVP
0.81

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: rs75622274; hg19: chr17-42458426; API