rs2048504402

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM4 PP4_Moderate 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 16

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Glanzmann thrombasthenia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Glanzmann's thrombasthenia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Glanzmann thrombasthenia 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000419.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	NM_000419.5	MANE Select	c.3115_3119dupGAGTG	p.Ter1040TrpfsTer63	frameshift stop_lost	Exon 30 of 30	NP_000410.2	P08514-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.3115_3119dupGAGTG	p.Ter1040TrpfsTer63	frameshift stop_lost	Exon 30 of 30	ENSP00000262407.5	P08514-1
	ITGA2B	ENST00000901307.1		c.3001_3005dupGAGTG	p.Ter1002TrpfsTer64	frameshift stop_lost	Exon 29 of 29	ENSP00000571366.1
	ITGA2B	ENST00000949677.1		c.2998_3002dupGAGTG	p.Ter1001TrpfsTer63	frameshift stop_lost	Exon 29 of 29	ENSP00000619736.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Glanzmann thrombasthenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
Mutation Taster		=20/180	disease causing

Splicing

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

Other links and lift over

dbSNP: rs2048504402; hg19: chr17-42449732;