17-44378642-C-T

Variant names:

• chr17-44378642-C-T
• rs746091910
• NM_000419.5:c.1946+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The splicing variant, c.1946+1G>A, has been observed in at least one compound heterozygous patient in the literature with a phenotype highly specific to GT (PMID:15099289). The canonical IVS19+1 donor splice site is lost, which is expected to result in skipping of exon 19 causing a reading frame shift with 10 new amino acids followed by a stop codon that leads to NMD. The variant is absent form ExAC, gnomAD, and 1000 Genomes. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8602901/MONDO:0010119/011

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ITGA2B NM_000419.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 6.63
• Publications: 1 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: Pathogenic. The variant received 11 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.
• 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.1946+1G>A		splice_donor_variant, intron_variant	Intron 19 of 29	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.2099+1G>A		splice_donor_variant, intron_variant	Intron 19 of 28		XP_011523051.2
ITGA2B	XM_011524750.2	c.2099+1G>A		splice_donor_variant, intron_variant	Intron 19 of 28		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.1946+1G>A		splice_donor_variant, intron_variant	Intron 19 of 29	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.1376+1G>A		splice_donor_variant, intron_variant	Intron 15 of 24			ENSP00000498119.1
ITGA2B	ENST00000592462.5	n.741+1G>A		splice_donor_variant, intron_variant	Intron 8 of 14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000569 AC: 1 AN: 175736 AF XY: 0.0000108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000756

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1414684 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 699102

African (AFR) AF: 0.00 AC: 0 AN: 32572

American (AMR) AF: 0.00 AC: 0 AN: 36776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25284

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37418

South Asian (SAS) AF: 0.00 AC: 0 AN: 80426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087460

Other (OTH) AF: 0.0000170 AC: 1 AN: 58666

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000839 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:2

Sep 06, 2020

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The splicing variant, c.1946+1G>A, has been observed in at least one compound heterozygous patient in the literature with a phenotype highly specific to GT (PMID: 15099289). The canonical IVS19+1 donor splice site is lost, which is expected to result in skipping of exon 19 causing a reading frame shift with 10 new amino acids followed by a stop codon that leads to NMD. The variant is absent form ExAC, gnomAD, and 1000 Genomes. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PP4_Moderate. -

Aug 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 19 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with autosomal recessive Glanzmann thrombasthenia (PMID: 15099289). This variant is also known as IVS19(+1). ClinVar contains an entry for this variant (Variation ID: 569057). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	31
DANN	Benign	0.94
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.6
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 3
DS_DL_spliceai		0.50		Position offset: 1

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

Other links and lift over

dbSNP: rs746091910; hg19: chr17-42456010;