17-44372407-C-T

Variant names:

• chr17-44372407-C-T
• rs879255514
• NM_000419.5:c.3077G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM3 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.5:c.3077G>A variant results in the Arg1026Gln missense change. It is absent in population databases, including gnomADv2.1.1 (PM2_supporting), and is predicted damaging by in silico tools (REVEL score of 0.904; PP3). One compound heterozygous individual with mild bleeding, thrombocytopenia and platelet anisotrpy is reported in the literature several times (PMID:25728920) with confirmation of c.1440-13_1440-1del (classified Pathogenic by the PD VCEP; PM3) in trans. The variant results in reduced expression of the αIIbβ3 complex on platelet surface. The expressed αIIbβ3 was not constitutively active and were able to bind fibrinogen only upon activation by anti-LIBS antibody. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM3, PP3 (PD VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10575572/MONDO:0010119/011

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:3
• Conservation: PhyloP100: 4.08
• Publications: 4 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000419.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	NM_000419.5	MANE Select	c.3077G>A	p.Arg1026Gln	missense	Exon 30 of 30	NP_000410.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.3077G>A	p.Arg1026Gln	missense	Exon 30 of 30	ENSP00000262407.5
	ITGA2B	ENST00000648408.1		c.2390G>A	p.Arg797Gln	missense	Exon 25 of 25	ENSP00000498119.1
	ITGA2B	ENST00000587295.5	TSL:3	c.269G>A	p.Arg90Gln	missense	Exon 3 of 3	ENSP00000467269.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251278 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461860 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Platelet-type bleeding disorder 16 Pathogenic:2

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not specified Uncertain:1

Apr 07, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ITGA2B c.3077G>A (p.Arg1026Gln, also known as p.Arg995Gln in literatures) results in a conservative amino acid change located in the cytoplasmic domain (Peyruchaud_1998) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, multiple structural studies showed alphaIIb R995/beta D732 salt bridge confers stability on the inactive state of integrin, supporting this residue is important for protein function (Ghevaert_2007, Yang_2009, Jayo_2010). The variant allele was found at a frequency of 4e-06 in 251278 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3077G>A has been reported in the literature in individuals affected with Glanzmann Thrombasthenia-Like Syndrome (Nurden_2015, French_1997, Peyruchaud_1998, Morais_2020). These data do not allow any conclusion about variant significance. At least one functional study reports this variant decreases surface alphaIIb -beta3 expression by approximately 50% of WT in cells and the mutated complex was not in a high activation state but remained functional in that activation could be induced by the anti-LIBS6 antibody (Peyruchaud_1998). Two ClinVar submitters (evaluation after 2014), including one expert panel (ClinGen Platelet Disorders Variant Curation Expert Panel,ClinGen), cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Glanzmann thrombasthenia Uncertain:1

Sep 07, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000419.5:c.3077G>A variant results in the Arg1026Gln missense change. It is absent in population databases, including gnomADv2.1.1 (PM2_supporting), and is predicted damaging by in silico tools (REVEL score of 0.904; PP3). One compound heterozygous individual with mild bleeding, thrombocytopenia and platelet anisotrpy is reported in the literature several times (PMID: 25728920) with confirmation of c.1440-13_1440-1del (classified Pathogenic by the PD VCEP; PM3) in trans. The variant results in reduced expression of the αIIbβ3 complex on platelet surface. The expressed αIIbβ3 was not constitutively active and were able to bind fibrinogen only upon activation by anti-LIBS antibody. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM3, PP3 (PD VCEP specifications version 2.1).

Thrombocytopenia Uncertain:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.1
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.96		Loss of MoRF binding (P = 0.0901)
MVP		0.92
MPC		1.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.96
gMVP		0.84
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879255514; hg19: chr17-42449775;