chr17-44372424-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2_SupportingPM3_SupportingPVS1_StrongPP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.3061-1G>A occurs within the canonical splice acceptor site of intron 29. It is predicted to cause skipping of biologically-relevant-exon 29, resulting in the in-frame deletion of 39 amino acids (3.7% of the protein) of the transmembrane region, which is considered a critical region by the PD-EP (PVS1_strong). At least one patient (GT31 in PMID:25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). GT31 is compound heterozygous for c.1771dup (classified Pathogenic by the PD-EP) and c.3061-1G>A (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PP4_strong, PM2_supporting, PM3_supporting. (VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA399787972/MONDO:0100326/011

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITGA2B
NM_000419.5 splice_acceptor, intron

Scores

2
4
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic reviewed by expert panel P:1

Conservation

PhyloP100: 4.06
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 10 ACMG points.

PVS1
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.
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.3061-1G>A splice_acceptor_variant, intron_variant Intron 29 of 29 ENST00000262407.6 NP_000410.2 P08514-1
ITGA2BXM_011524749.2 linkc.3112-1G>A splice_acceptor_variant, intron_variant Intron 28 of 28 XP_011523051.2 P08514
ITGA2BXM_011524750.2 linkc.3097-1G>A splice_acceptor_variant, intron_variant Intron 28 of 28 XP_011523052.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITGA2BENST00000262407.6 linkc.3061-1G>A splice_acceptor_variant, intron_variant Intron 29 of 29 1 NM_000419.5 ENSP00000262407.5 P08514-1
ITGA2BENST00000648408.1 linkc.2374-1G>A splice_acceptor_variant, intron_variant Intron 24 of 24 ENSP00000498119.1 A0A3B3IU79
ITGA2BENST00000587295.5 linkc.253-1G>A splice_acceptor_variant, intron_variant Intron 2 of 2 3 ENSP00000467269.1 K7EP83

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461822
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727206
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1
Pathogenic, reviewed by expert panelcurationClinGen Platelet Disorders Variant Curation Expert Panel, ClinGenAug 05, 2022The NM_000419.5(ITGA2B):c.3061-1G>A occurs within the canonical splice acceptor site of intron 29. It is predicted to cause skipping of biologically-relevant-exon 29, resulting in the in-frame deletion of 39 amino acids (3.7% of the protein) of the transmembrane region, which is considered a critical region by the PD-EP (PVS1_strong). At least one patient (GT31 in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). GT31 is compound heterozygous for c.1771dup (classified Pathogenic by the PD-EP) and c.3061-1G>A (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PP4_strong, PM2_supporting, PM3_supporting. (VCEP specifications version 2.1). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
29
DANN
Uncertain
0.99
Eigen
Pathogenic
0.78
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.95
D
GERP RS
4.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.56
Position offset: -2
DS_AL_spliceai
0.98
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-42449792; COSMIC: COSV99288726; COSMIC: COSV99288726; API