NM_000419.5:c.818G>A

Variant names:

• chr17-44384567-C-T
• rs137852907
• NM_000419.5:c.818G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4_Moderate PP3 PM2_Supporting PS3_Moderate PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.818G>A (p.Gly273Asp) variant has been reported, in the homozygous state (PM3_supporting), in at least one proband (PMID:8282784) with a GT-specific phenotype. The patient in PMID:8282784 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, the patient had <5% expression by flow cytometry. The variant is absent from gnomADv4.0 (PM2_supporting) and is predicted deleterious (REVEL score 0.845; PP3). 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 Gly273Asp 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 Gly273Asp. PMID:8916916 reports similar immunoprecipitation results. 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, PM2_supporting, PM3_supporting, PP3, and PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115837/MONDO:0010119/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 2.69
• Publications: 9 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: Likely_pathogenic. The variant received 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.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.818G>A	p.Gly273Asp	missense_variant	Exon 8 of 30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.971G>A	p.Gly324Asp	missense_variant	Exon 8 of 29		XP_011523051.2
ITGA2B	XM_011524750.2	c.971G>A	p.Gly324Asp	missense_variant	Exon 8 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.818G>A	p.Gly273Asp	missense_variant	Exon 8 of 30	1	NM_000419.5	ENSP00000262407.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1

May 02, 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.818G>A (p.Gly273Asp) variant has been reported, in the homozygous state (PM3_supporting), in at least one proband (PMID: 8282784) with a GT-specific phenotype. The patient in PMID: 8282784 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, the patient had <5% expression by flow cytometry. The variant is absent from gnomADv4.0 (PM2_supporting) and is predicted deleterious (REVEL score 0.845; PP3). 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 Gly273Asp 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 Gly273Asp. PMID: 8916916 reports similar immunoprecipitation results. 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, PM2_supporting, PM3_supporting, PP3, and PP4_moderate. -

Glanzmann thrombasthenia 1 Pathogenic:1

Jan 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		2.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.87		Gain of sheet (P = 0.0827);
MVP		0.91
MPC		2.3
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.92
gMVP		0.98
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137852907; hg19: chr17-42461935;