rs80002943

Variant names:

• chr17-44374732-G-A
• rs80002943
• NM_000419.5:c.2870C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PS3_Supporting PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2870C>T; p.Ser957Leu variant has been reported, in the homozygous state, in at least one proband (PMID:20020534). It is absent from population databases ExAC and gnomAD. The Ser957Leu mutant complex was expressed in COS-7 cells and, in three replicates, expression of the complex (% positive cells) was assessed by flow cytometry, using antibodies to alpha-IIb, beta-3 or the complex, finding approximately 19% positive cells for the αIIbβ3 complex compared to WT. In summary, this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PS3_supporting, PM2_Supporting and PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115850/MONDO:0010119/011

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 4.46

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA2B	NM_000419.5	c.2870C>T	p.Ser957Leu	missense_variant	Exon 28 of 30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524750.2	c.3023C>T	p.Ser1008Leu	missense_variant	Exon 28 of 29		XP_011523052.2
ITGA2B	XM_011524749.2	c.2995-262C>T		intron_variant	Intron 27 of 28		XP_011523051.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.2870C>T	p.Ser957Leu	missense_variant	Exon 28 of 30	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.2300C>T	p.Ser767Leu	missense_variant	Exon 24 of 25			ENSP00000498119.1
ITGA2B	ENST00000587295.5	c.252+1101C>T		intron_variant	Intron 2 of 2	3		ENSP00000467269.1
ITGA2B	ENST00000592462.5	n.2381C>T		non_coding_transcript_exon_variant	Exon 15 of 15	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia 1 Pathogenic:1

Mar 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

May 09, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ITGA2B c.2870C>T (p.Ser957Leu) results in a non-conservative amino acid change located in the Integrin alpha, third immunoglobulin-like domain (IPR048286) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250924 control chromosomes. c.2870C>T has been reported in the literature in homozygous state in one individual affected with Glanzmann thrombasthenia 1 (Jallu_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced (approximately 33% of WT) "alpha IIb beta3" Fibrinogen receptor complex expression at the surface of Cos-7 cells that correlated with 10% beta3 expression at the surface of patient platelets (Jallu_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20020534). ClinVar contains an entry for this variant (Variation ID: 2902). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Glanzmann thrombasthenia Uncertain:1

Mar 16, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.2870C>T; p.Ser957Leu variant has been reported, in the homozygous state, in at least one proband (PMID: 20020534). It is absent from population databases ExAC and gnomAD. The Ser957Leu mutant complex was expressed in COS-7 cells and, in three replicates, expression of the complex (% positive cells) was assessed by flow cytometry, using antibodies to alpha-IIb, beta-3 or the complex, finding approximately 19% positive cells for the αIIbβ3 complex compared to WT. In summary, this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PS3_supporting, PM2_Supporting and PM3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.93		Loss of sheet (P = 0.1907);
MVP		0.83
MPC		0.92
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.54
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80002943; hg19: chr17-42452100;