chr17-44380385-C-T

Position:

• chr17-44380385-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP4_Strong PM3 PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000419.5(ITGA2B):c.1544+1G>A is a canonical splice donor variant on intron 15 of ITGA2B, that was demonstrated to result in a frameshift leading to a premature stop codon due to abnormal splicing occuring in a cryptic splice site located 8 bp upstream from the mutation (PMIDs: 7620188, 21487445). This variant has been reported several times in French Manouche families with a GT phenotype. It has been reported to occur in a homozygous state in at least 16 individuals (PMIDs: 25728920, 22250950). It is absent from large population cohorts including gnomAD. This variant satisfies GT specific criteria for PVS1, PM3, PP4_Strong and PM2_Supporting and is therefore classified as Pathogenic for GT. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10575473/MONDO:0010119/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGA2B NM_000419.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 4.25

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 15 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA2B	NM_000419.5	c.1544+1G>A		splice_donor_variant		ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.1697+1G>A		splice_donor_variant			XP_011523051.2
ITGA2B	XM_011524750.2	c.1697+1G>A		splice_donor_variant			XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.1544+1G>A		splice_donor_variant		1	NM_000419.5	ENSP00000262407	P1
ITGA2B	ENST00000648408.1	c.975+1G>A		splice_donor_variant				ENSP00000498119
ITGA2B	ENST00000592226.5	n.1017+1G>A		splice_donor_variant, non_coding_transcript_variant		5
ITGA2B	ENST00000592462.5	n.339+1G>A		splice_donor_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Jan 19, 2021

NM_000419.5(ITGA2B):c.1544+1G>A is a canonical splice donor variant on intron 15 of ITGA2B, that was demonstrated to result in a frameshift leading to a premature stop codon due to abnormal splicing occuring in a cryptic splice site located 8 bp upstream from the mutation (PMIDs: 7620188, 21487445). This variant has been reported several times in French Manouche families with a GT phenotype. It has been reported to occur in a homozygous state in at least 16 individuals (PMIDs: 25728920, 22250950). It is absent from large population cohorts including gnomAD. This variant satisfies GT specific criteria for PVS1, PM3, PP4_Strong and PM2_Supporting and is therefore classified as Pathogenic for GT. -

Glanzmann thrombasthenia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs879255509; hg19: chr17-42457753;