rs78657866

chr17-44374470-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_000419.5(ITGA2B):c.2944G>A(p.Val982Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. V982V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ITGA2B NM_000419.5 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 2.45

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 10 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-44374470-C-T is Pathogenic according to our data. Variant chr17-44374470-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 381747.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.2944G>A	p.Val982Met	missense_variant, splice_region_variant	29/30	ENST00000262407.6
ITGA2B	XM_011524749.2	c.2995G>A	p.Val999Met	missense_variant, splice_region_variant	28/29
ITGA2B	XM_011524750.2	c.3096+189G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.2944G>A	p.Val982Met	missense_variant, splice_region_variant	29/30	1	NM_000419.5	P1
ITGA2B	ENST00000587295.5	c.253+1363G>A		intron_variant		3
ITGA2B	ENST00000648408.1	c.2374+189G>A		intron_variant
ITGA2B	ENST00000592462.5	n.2643G>A		non_coding_transcript_exon_variant	15/15	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461518 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727102

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Sep 06, 2020

The c.2944G>A (p.Val982Met) missense variant has been reported in at least three compound heterozygous probands with a phenotype highly specific to GT (PMID: 28983057, 25539746,15099289); one of which was a de novo occurrence (PMID: 25539746). It is found at an extremely low frequency (MAF of 0.00006486 in the non-Finnish European population from gnomAD). This variant is predicted by HSF and MaxEntScan to result in a broken splice donor site. Flow cytometry found that this variant had a marked deleterious effect on αIIbβ3 expression (~25% of control levels) in COS-7 cells (PMID: 15099289). In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PS2, PM3, PM2_supporting, PS3_Moderate, PP3, and PP4_moderate. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 27, 2016

The V982M variant in the ITGA2B gene has been reported previously (as V951M due to the use of alternate nomenclature) in assocation with Glanzmann thrombasthenia (Nurden et al., 2004; Jallu et al., 2010). In one individual, V982M was identified in the compound heterozygous state with a splice site variant (Nurden et al., 2004), while in another individual, no second pathogenic variant was identified (Jallu et al., 2010). The V982M variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V982M variant is a conservative amino acid substitution, which occurs at a position that is conserved in mammals. Functional studies demonstrate that V982M results in significant loss of ITGA2b protein surface expression (Nurden et al., 2004). The V982M variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Glanzmann thrombasthenia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.97	A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.33
Sift	Benign	0.089	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.35
MutPred		0.77		Loss of sheet (P = 0.0817);
MVP		0.77
MPC		0.97
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.24
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.19		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: rs78657866; hg19: chr17-42451838;