17-44372424-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong

The NM_000419.5(ITGA2B):c.3061-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITGA2B
NM_000419.5 splice_acceptor

Scores

Splicing: ADA: 1.000

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]

ITGA2B links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.077564105 fraction of the gene.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-44372424-C-T is Pathogenic according to our data. Variant chr17-44372424-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1879037.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
ITGA2B	NM_000419.5 linkuse as main transcript	c.3061-1G>A	splice_acceptor_variant	ENST00000262407.6
ITGA2B	XM_011524749.2 linkuse as main transcript	c.3112-1G>A	splice_acceptor_variant
ITGA2B	XM_011524750.2 linkuse as main transcript	c.3097-1G>A	splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6 linkuse as main transcript	c.3061-1G>A	splice_acceptor_variant	1	NM_000419.5	P1	P08514-1
ITGA2B	ENST00000587295.5 linkuse as main transcript	c.254-1G>A	splice_acceptor_variant	3
ITGA2B	ENST00000648408.1 linkuse as main transcript	c.2375-1G>A	splice_acceptor_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

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 panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Aug 05, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

-0.050

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

D;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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over