rs137852906

Variant names:

• chr17-44380004-G-A
• rs137852906
• NM_000419.5:c.1750C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-44380004-G-A
• chr17-44380004-G-C
• chr17-44380004-G-T

Variant summary

Our verdict is Pathogenic. The variant received 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:5
• Conservation: PhyloP100: 2.13
• Publications: 13 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 12 ACMG points.

• PVS1: 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.1750C>T	p.Arg584*	stop_gained, splice_region_variant	Exon 17 of 30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.1903C>T	p.Arg635*	stop_gained, splice_region_variant	Exon 17 of 29		XP_011523051.2
ITGA2B	XM_011524750.2	c.1903C>T	p.Arg635*	stop_gained, splice_region_variant	Exon 17 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.1750C>T	p.Arg584*	stop_gained, splice_region_variant	Exon 17 of 30	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.1180C>T	p.Arg394*	stop_gained, splice_region_variant	Exon 13 of 25			ENSP00000498119.1
ITGA2B	ENST00000592462.5	n.545C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 15	5
ITGA2B	ENST00000592226.5	n.*53C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250734 AF XY: 0.00000736

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5094

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

Other (OTH) AF: 0.0000332 AC: 2 AN: 60318

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:2

Sep 04, 2020

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Dec 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Platelet-type bleeding disorder 16;CN300358:Glanzmann thrombasthenia 1 Pathogenic:2

Feb 21, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM3_VeryStrong+PP4_Strong -

Glanzmann thrombasthenia 1 Pathogenic:1

Jun 15, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		2.1
Vest4		0.81
GERP RS		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852906; hg19: chr17-42457372; COSMIC: COSV52231757; COSMIC: COSV52231757;