NM_000419.5:c.409-2_419delAGGCCTGCGCCCC

Variant names:

• chr17-44385705-GGGGGCGCAGGCCT-G
• rs879255508
• NM_000419.5:c.409-2_419delAGGCCTGCGCCCC

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PP4_Strong PM3 PM2_Supporting PS3 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 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 8.06
• Publications: 0 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	NM_000419.5	MANE Select	c.409-2_419delAGGCCTGCGCCCC	p.Ala137fs	frameshift splice_acceptor splice_region intron	Exon 4 of 30	NP_000410.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.409-2_419delAGGCCTGCGCCCC	p.Ala137fs	frameshift splice_acceptor splice_region intron	Exon 4 of 30	ENSP00000262407.5
	ITGA2B	ENST00000592944.1	TSL:5	n.92_104delAGGCCTGCGCCCC		non_coding_transcript_exon	Exon 1 of 6

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs879255508; hg19: chr17-42463073;