chr17-44380004-G-A

Position:

• chr17-44380004-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000419.4:c.1750C>T that leads to Arg584Ter is a nonsense variant that has been reported in several GT patients meeting phenotype criteria in the homozygous as well as compound heterozygous states (PMIDs: 25728920, 28888044, 22250950, 9215749, 29675921). It is reported at a frequency >0.0001 in the combined gnomAD v3 and v2.1.1 datasets. This nonsense variant occurs in exon 17 out of 30 and is predicted to result in NMD. In summary, this variant meets criteria to be classified as pathogenic. GT-specific codes applied: PVS1, PP4_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115834/MONDO:0010119/011

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ITGA2B NM_000419.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 2.13

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 12 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.1750C>T	p.Arg584Ter	stop_gained, splice_region_variant	17/30	ENST00000262407.6
ITGA2B	XM_011524749.2	c.1903C>T	p.Arg635Ter	stop_gained, splice_region_variant	17/29
ITGA2B	XM_011524750.2	c.1903C>T	p.Arg635Ter	stop_gained, splice_region_variant	17/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.1750C>T	p.Arg584Ter	stop_gained, splice_region_variant	17/30	1	NM_000419.5	P1
ITGA2B	ENST00000648408.1	c.1183C>T	p.Arg395Ter	stop_gained, splice_region_variant	13/25
ITGA2B	ENST00000592462.5	n.545C>T		splice_region_variant, non_coding_transcript_exon_variant	6/15	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250734 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461054 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Sep 04, 2020	The NM_000419.4:c.1750C>T that leads to Arg584Ter is a nonsense variant that has been reported in several GT patients meeting phenotype criteria in the homozygous as well as compound heterozygous states (PMIDs: 25728920, 28888044, 22250950, 9215749, 29675921). It is reported at a frequency >0.0001 in the combined gnomAD v3 and v2.1.1 datasets. This nonsense variant occurs in exon 17 out of 30 and is predicted to result in NMD. In summary, this variant meets criteria to be classified as pathogenic. GT-specific codes applied: PVS1, PP4_strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	This sequence change creates a premature translational stop signal (p.Arg584*) in the ITGA2B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ITGA2B are known to be pathogenic (PMID: 21917754). This variant is present in population databases (rs137852906, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Glanzmann’s thrombasthenia (PMID: 1317725, 22190468, 30138987). ClinVar contains an entry for this variant (Variation ID: 2892). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Glanzmann thrombasthenia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A
Vest4		0.81
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.0		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: rs137852906; hg19: chr17-42457372; COSMIC: COSV52231757; COSMIC: COSV52231757;