rs1555613692

Variant names:

• chr17-44378360-A-G
• rs1555613692
• NM_000419.5:c.2094+2T>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.2094+2T>C splice variant is predicted to cause skipping of exon 20, introducing a premature termination codon, and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual reported to have Glanzmann's thrombasthenia (GT), however sufficient phenotype information was not provided to determine if the individual's phenotype is specific for GT. This variant is absent from population databases, including gnomAD. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, and PM3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA399799489/MONDO:0010119/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGA2B NM_000419.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9851
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 5.46

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: 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.2094+2T>C		splice_donor_variant, intron_variant	Intron 20 of 29	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.2247+2T>C		splice_donor_variant, intron_variant	Intron 20 of 28		XP_011523051.2
ITGA2B	XM_011524750.2	c.2247+2T>C		splice_donor_variant, intron_variant	Intron 20 of 28		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.2094+2T>C		splice_donor_variant, intron_variant	Intron 20 of 29	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.1524+2T>C		splice_donor_variant, intron_variant	Intron 16 of 24			ENSP00000498119.1
ITGA2B	ENST00000592462.5	n.889+2T>C		splice_donor_variant, intron_variant	Intron 9 of 14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:2

May 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 20 of the ITGA2B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ITGA2B are known to be pathogenic (PMID: 21917754). This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Glanzmann thrombasthenia (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 458368). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. -

May 07, 2021

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000419.5(ITGA2B):c.2094+2T>C splice variant is predicted to cause skipping of exon 20, introducing a premature termination codon, and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual reported to have Glanzmann's thrombasthenia (GT), however sufficient phenotype information was not provided to determine if the individual's phenotype is specific for GT. This variant is absent from population databases, including gnomAD. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, and PM3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555613692; hg19: chr17-42455728;