rs121918451

chr17-47300488-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000212.3(ITGB3):c.1924G>T(p.Glu642Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,226 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 Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ITGB3 NM_000212.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.06

Genes affected

ITGB3 (HGNC:6156): (integrin subunit beta 3) The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-47300488-G-T is Pathogenic according to our data. Variant chr17-47300488-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13565.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB3	NM_000212.3	c.1924G>T	p.Glu642Ter	stop_gained	12/15	ENST00000559488.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB3	ENST00000559488.7	c.1924G>T	p.Glu642Ter	stop_gained	12/15	1	NM_000212.3	P1
ITGB3	ENST00000696963.1	c.1924G>T	p.Glu642Ter	stop_gained	12/14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461226 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726994

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 21, 2021

NM_000212.2(ITGB3):c.1924G>T (p.Glu642Ter) in exon 12 of 15 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. However, RT-PCR analysis in the proband of PMID: 9845537 found that, instead, a shortened transcript was produced (in similar quantities to the normal allele) with in-frame skipping of exons 11 and 12 (reported by authors as exons 10 and 11, using alternate numbering), resulting in removal of 14% of the protein (PVS1_strong). CHO cells were transiently cotransfected with the plasmid pcDNA3-GPIIb and either WT or mutant pcDNA3-GPIIIa with this variant. To investigate the surface exposure of GPIIb-IIIa, intact cells were labeled with biotin, and the GPIIb-IIIa complexes were immunoprecipitated with anti-GPIIb (M3) or anti-GPIIIa (P37) MoAbs. No biotin-labeled products were found in cells cotransfected with normal GPIIb and mutant GPIIIa. Additionally, to examine the intracellular presence of GPIIb and/or GPIIIa as either monomers or heterodimers, total cell lysates were labeled with biotin, and GPIIb, GPIIIa, or GPIIb-IIIa complexes were immunoprecipitated. Unlike in extracts from cells coexpressing normal subunits, heterodimers failed to immunoprecipitate using a complex-specific MoAb, suggesting that the mutant ΔGPIIIa does not complex with GPIIb. Pulse-chase experiments further verified that the mutant ΔGPIIIa does not complex to GPIIb (PMID: 9845537; PS3_supporting). This variant has been detected homozygous in at least 2 probands with Glanzmann thrombasthenia (PMIDs: 14985172, 9845537; PM3). At least one patient (Patient II.1 in PMID: 14985172) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry and Western blot. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PS3_supporting, PP4_moderate, PM3, PM2_supporitng. (VCEP specifications version 2; date of approval 12/21/21). -

Glanzmann thrombasthenia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 1998

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 18, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 13565). This premature translational stop signal has been observed in individual(s) with Glanzmann thrombasthenia (PMID: 9845537). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu642*) in the ITGB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ITGB3 are known to be pathogenic (PMID: 21917754). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	51
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.97
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121918451; hg19: chr17-45377854;