17-44372407-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM5 PP3_Strong

The NM_000419.5(ITGA2B):c.3077G>A(p.Arg1026Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1026A) has been classified as Uncertain significance.

• 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

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain Integrin alpha-IIb light chain, form 1 (size 148) in uniprot entity ITA2B_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_000419.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44372408-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 50233.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=7, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.3077G>A	p.Arg1026Gln	missense_variant	30/30	ENST00000262407.6
ITGA2B	XM_011524749.2	c.3128G>A	p.Arg1043Gln	missense_variant	29/29
ITGA2B	XM_011524750.2	c.3113G>A	p.Arg1038Gln	missense_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.3077G>A	p.Arg1026Gln	missense_variant	30/30	1	NM_000419.5	P1
ITGA2B	ENST00000648408.1	c.2393G>A	p.Arg798Gln	missense_variant	25/25
ITGA2B	ENST00000587295.5	c.272G>A	p.Arg91Gln	missense_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251278 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135860

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2011	- -

Glanzmann thrombasthenia Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Sep 07, 2023

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). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 07, 2022

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. -

Thrombocytopenia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs879255514; hg19: chr17-42449775;