17-44372364-T-TCACTC

Variant names:

• chr17-44372364-T-TCACTC
• rs2048504402
• NM_000419.5:c.3115_3119dupGAGTG

Variant summary

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

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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
ITGA2B	NM_000419.5	c.3115_3119dupGAGTG	p.Ter1040TrpfsTer63	frameshift_variant, stop_lost	Exon 30 of 30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.3166_3170dupGAGTG	p.Ter1057TrpfsTer63	frameshift_variant, stop_lost	Exon 29 of 29		XP_011523051.2
ITGA2B	XM_011524750.2	c.3151_3155dupGAGTG	p.Ter1052TrpfsTer63	frameshift_variant, stop_lost	Exon 29 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.3115_3119dupGAGTG	p.Ter1040TrpfsTer63	frameshift_variant, stop_lost	Exon 30 of 30	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.2428_2432dupGAGTG	p.Ter811fs	frameshift_variant, stop_lost	Exon 25 of 25			ENSP00000498119.1
ITGA2B	ENST00000587295.5	c.307_311dupGAGTG	p.Ter104fs	frameshift_variant, stop_lost	Exon 3 of 3	3		ENSP00000467269.1

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

Aug 15, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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;