17-44372391-CA-C

Variant names:

• chr17-44372391-CA-C
• NM_000419.5:c.3092delT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2_Supporting PM4 PP4_Strong PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.3092del (p.Leu1031ArgfsTer?) variant causes a frameshift and subsequent stop loss. This results in the addition of 90 amino acids to the ITGA2B protein, beyond the cytoplasmic domain (PM4). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient (Patient GT11 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced between 5% and 20% and function was pathological, as measured by flow cytometry (PP4_strong). This patient is compound heterozygous for the maternal c.3092del variant and Leu214Pro (classified Pathogenic by the PD-EP), without confirmation of trans phase (PM3_supporting). In summary this variant meets 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: PP4_strong, PM2_supporting, PM3_supporting, PM4. (VCEP specifications version 2; date of approval xx/xx/xxxx) LINK:https://erepo.genome.network/evrepo/ui/classification/CA915940323/MONDO:0100326/011

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ITGA2B NM_000419.5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 2.94

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 8 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.3092delT	p.Leu1031ArgfsTer70	frameshift_variant	Exon 30 of 30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.3143delT	p.Leu1048ArgfsTer70	frameshift_variant	Exon 29 of 29		XP_011523051.2
ITGA2B	XM_011524750.2	c.3128delT	p.Leu1043ArgfsTer70	frameshift_variant	Exon 29 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.3092delT	p.Leu1031ArgfsTer70	frameshift_variant	Exon 30 of 30	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.2405delT	p.Leu802fs	frameshift_variant	Exon 25 of 25			ENSP00000498119.1
ITGA2B	ENST00000587295.5	c.284delT	p.Leu95fs	frameshift_variant	Exon 3 of 3	3		ENSP00000467269.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1

Dec 02, 2021

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.3092del (p.Leu1031ArgfsTer?) variant causes a frameshift and subsequent stop loss. This results in the addition of 90 amino acids to the ITGA2B protein, beyond the cytoplasmic domain (PM4). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient (Patient GT11 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, alphaIIbbeta3 surface expression was reduced between 5% and 20% and function was pathological, as measured by flow cytometry (PP4_strong). This patient is compound heterozygous for the maternal c.3092del variant and Leu214Pro (classified Pathogenic by the PD-EP), without confirmation of trans phase (PM3_supporting). In summary this variant meets 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: PP4_strong, PM2_supporting, PM3_supporting, PM4. (VCEP specifications version 2; date of approval xx/xx/xxxx) -

Platelet-type bleeding disorder 16;CN300358:Glanzmann thrombasthenia 1 Pathogenic:1

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glanzmann thrombasthenia 1 Pathogenic:1

Mar 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ITGA2B c.3092delT (p.Leu1031ArgfsX70+) causes a frameshift which results in an extension of the protein. This variant results in the addition of 90 amino acids to the ITGA2B protein, beyond the cytoplasmic domain. The variant was absent in 251356 control chromosomes. c.3092delT has been reported in the literature in at-least two individuals affected with Glanzmann thrombasthenia, in each case, it was at a compound heterozygous along with a different pathogenic missense (example, Sandrock-Lang_2015, Sharma_2021). These data indicate that the variant may be associated with disease. Additionally, a similar extension variant c.3091delC variant causes a frameshift Leu1031TrpfsTer97 and subsequent stop loss, also adds 90 amino acids to the ITGA2B protein, and was evaluated Likely Pathogenic per ClinGen Platelet Disorders Variant Curation Expert Panel (ClinVar ID 1879040). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25373348, 34267460). ClinVar contains an entry for this variant (Variation ID: 1691488). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-42449759;