rs780017389

Variant names:

• chr17-44380900-TGTCTAC-T
• rs780017389
• NM_000419.5:c.1366_1371delGTAGAC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_Moderate PM2_Supporting PS3_Moderate PM4

This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.1366_1371del (p.Val456_Asp457del) variant causes an in-frame deletion of two amino acids (PM4). It has been reported, in at least one GT proband (PMID:8704171). Patient LeM of PMID:8704171 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, there was reduced surface expression of aIIbß3 measured by flow cytometry. This variant is absent from gnomAD v4.0.0 (PM2_Supporting). Heterologous expression followed by the preferred assays, of either Western blot or flow cytometry, has not been reported for this variant. However in PMID:8282784, to test for mutant complexes on the cell surface, COS-1 cells were cotransfected with WT ITGB3 and Val456_Asp457del ITGA2B, cells were surface labeled with 125I and immunoprecipitated, then labeled heterodimers were detected on the surface of cotransfected cells containing wildtype ITGA2B but not on the surface of cells containing Val456_Asp457del ITGA2B. These results were considered sufficient evidence of impaired surface expression for application of the PS3_moderate criteria. In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PS3_moderate,PP4_Moderate, PM4, and PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8603160/MONDO:0010119/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGA2B NM_000419.5 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 6.13

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 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.1366_1371delGTAGAC	p.Val456_Asp457del	conservative_inframe_deletion	Exon 13 of 30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.1519_1524delGTAGAC	p.Val507_Asp508del	conservative_inframe_deletion	Exon 13 of 29		XP_011523051.2
ITGA2B	XM_011524750.2	c.1519_1524delGTAGAC	p.Val507_Asp508del	conservative_inframe_deletion	Exon 13 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.1366_1371delGTAGAC	p.Val456_Asp457del	conservative_inframe_deletion	Exon 13 of 30	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.796_801delGTAGAC	p.Val266_Asp267del	conservative_inframe_deletion	Exon 9 of 25			ENSP00000498119.1
ITGA2B	ENST00000592226.5	n.606_611delGTAGAC		non_coding_transcript_exon_variant	Exon 7 of 10	5
ITGA2B	ENST00000592462.5	n.161_166delGTAGAC		non_coding_transcript_exon_variant	Exon 2 of 15	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1

Apr 16, 2024

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000419.5(ITGA2B):c.1366_1371del (p.Val456_Asp457del) variant causes an in-frame deletion of two amino acids (PM4). It has been reported, in at least one GT proband (PMID: 8704171). Patient LeM of PMID: 8704171 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, there was reduced surface expression of aIIbß3 measured by flow cytometry. This variant is absent from gnomAD v4.0.0 (PM2_Supporting). Heterologous expression followed by the preferred assays, of either Western blot or flow cytometry, has not been reported for this variant. However in PMID: 8282784, to test for mutant complexes on the cell surface, COS-1 cells were cotransfected with WT ITGB3 and Val456_Asp457del ITGA2B, cells were surface labeled with 125I and immunoprecipitated, then labeled heterodimers were detected on the surface of cotransfected cells containing wildtype ITGA2B but not on the surface of cells containing Val456_Asp457del ITGA2B. These results were considered sufficient evidence of impaired surface expression for application of the PS3_moderate criteria. In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PS3_moderate,PP4_Moderate, PM4, and PM2_supporting. -

Glanzmann thrombasthenia 1 Pathogenic:1

Jul 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: rs780017389; hg19: chr17-42458268;