17-44385705-GGGGGCGCAGGCCT-G

Position:

• chr17-44385705-GGGGGCGCAGGCCT-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2_Supporting PS3 PP4_Strong PM3 PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The c.409-2_419del variant was first reported in the Palestinian population by PMID:2014236; haplotype analysis in PMID:16359514 is consistent with a founder effect. This variant has also been described as c.409-3_418del and HGVS nomenclature is c.409-4_417del. The deletion causes use of a cryptic splice site at position c.425_426 (confirmed in patient mRNA in PMID:2014236). As such there is an in-frame deletion of 18bp encompassing 6 amino acids (Ala137 through Gln142) in the critical ligand binding beta-propeller domain. This variant is absent from all population databases, including gnomAD. The variant has been identified homozygous in at least 8 patients (PMIDs: 2014236, 16359514). with a phenotype highly specific to GT. Transfection in BHK cells resulted in lack of surface expression of αIIbβ3 (PMID:16359514). In summary this variant is classified as Pathogenic for GT. GT-specific criteria applied: PVS1_strong, PS3, PM2_supporting, PM3, PP4_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10575471/MONDO:0010119/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGA2B NM_000419.5 splice_acceptor, coding_sequence
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 8.06

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: 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/exons	MANE	Protein	UniProt
ITGA2B	NM_000419.5	c.409-2_419del		splice_acceptor_variant, coding_sequence_variant	4/30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.562-2_572del		splice_acceptor_variant, coding_sequence_variant	4/29		XP_011523051.2
ITGA2B	XM_011524750.2	c.562-2_572del		splice_acceptor_variant, coding_sequence_variant	4/29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.409-2_419del		splice_acceptor_variant, coding_sequence_variant	4/30	1	NM_000419.5	ENSP00000262407	P1
ITGA2B	ENST00000592944.1	n.92_104del		non_coding_transcript_exon_variant	1/6	5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

May 07, 2021

The c.409-2_419del variant was first reported in the Palestinian population by PMID: 2014236; haplotype analysis in PMID: 16359514 is consistent with a founder effect. This variant has also been described as c.409-3_418del and HGVS nomenclature is c.409-4_417del. The deletion causes use of a cryptic splice site at position c.425_426 (confirmed in patient mRNA in PMID: 2014236). As such there is an in-frame deletion of 18bp encompassing 6 amino acids (Ala137 through Gln142) in the critical ligand binding beta-propeller domain. This variant is absent from all population databases, including gnomAD. The variant has been identified homozygous in at least 8 patients (PMIDs: 2014236, 16359514). with a phenotype highly specific to GT. Transfection in BHK cells resulted in lack of surface expression of αIIbβ3 (PMID: 16359514). In summary this variant is classified as Pathogenic for GT. GT-specific criteria applied: PVS1_strong, PS3, PM2_supporting, PM3, PP4_strong. -

Glanzmann thrombasthenia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 12, 1991

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879255508; hg19: chr17-42463073;