chr17-44372364-T-TCACTC

Position:

• chr17-44372364-T-TCACTC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_Moderate PM4 PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The stop loss NM_000419.5(ITGA2B):c.3115_3119dup variant causes Ter1040Trp and extension of the protein by 92 amino acids (PM4). It has been observed in the homozygous state in one patient with a phenotype highly specific to GT, including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and <5% surface expression of αIIbβ3 measured by flow cytometry (PMID:19691478; PP4_moderate, PM3_supporting). This variant is absent from gnomADv2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM4, PP4_moderate, PM3_supporting (PD VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA915940262/MONDO:0010119/011

• Frequency: Genomes: not found (cov: 31)
• Consequence: ITGA2B NM_000419.5 frameshift, stop_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 0.808

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 Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.3119_3120insGAGTG	p.Ter1040TrpfsTer?	frameshift_variant, stop_lost	30/30	ENST00000262407.6
ITGA2B	XM_011524749.2	c.3170_3171insGAGTG	p.Ter1057TrpfsTer?	frameshift_variant, stop_lost	29/29
ITGA2B	XM_011524750.2	c.3155_3156insGAGTG	p.Ter1052TrpfsTer?	frameshift_variant, stop_lost	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.3119_3120insGAGTG	p.Ter1040TrpfsTer?	frameshift_variant, stop_lost	30/30	1	NM_000419.5	P1
ITGA2B	ENST00000587295.5	c.312_313insGAGTG	p.Ter105TrpfsTer?	frameshift_variant, stop_lost	3/3	3
ITGA2B	ENST00000648408.1	c.2433_2434insGAGTG	p.Ter812TrpfsTer?	frameshift_variant, stop_lost	25/25

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Aug 15, 2023

The stop loss NM_000419.5(ITGA2B):c.3115_3119dup variant causes Ter1040Trp and extension of the protein by 92 amino acids (PM4). It has been observed in the homozygous state in one patient with a phenotype highly specific to GT, including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and <5% surface expression of αIIbβ3 measured by flow cytometry (PMID: 19691478; PP4_moderate, PM3_supporting). This variant is absent from gnomADv2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM4, PP4_moderate, PM3_supporting (PD VCEP specifications version 2.1). -

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: rs2048504402; hg19: chr17-42449732;