rs121918446

Positions:

chr17-47286363-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3PM5PP4_ModeratePP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp) missense variant has been reported in at least five patients (PMID:32200672, 7509233, 1602006, doi.org/10.2491/jjsth.10.243, and a thesis by Zapelli in 2014) with a phenotype highly specific to GT. Several probands from PMID:32200672, PMID:7509233, and PMID:1602006 are homozygous (PM3) and meet the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, surface αIIbβ3 was dysfunctional as shown by defective PAC-1 and fibrinogen binding. This variant is at an extremely low frequency (below the <1/10,000 threshold) with a MAF of 0.00002196 (2/91,084 alleles) in the gnomADv4.1.0 South Asian population (PM2_supporting). It is predicted to have a deleterious effect (REVEL score 0.832; PP3) and occurs at the same residue as pathogenic variant Arg240Gln (PM5). In summary this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM5, PP3, and PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA123228/MONDO:0100326/011

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

9

7

2

Clinical Significance

Likely pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 2.17

Variant links:

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]

ITGB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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.

PM5

For more information check the summary or visit ClinGen Evidence Repository.

PP3

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/exons	MANE	Protein	UniProt
ITGB3	NM_000212.3 linkuse as main transcript	c.718C>T	p.Arg240Trp	missense_variant	5/15	ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7 linkuse as main transcript	c.718C>T	p.Arg240Trp	missense_variant	5/15	1	NM_000212.3	ENSP00000452786	P1	P05106-1
ITGB3	ENST00000571680.1 linkuse as main transcript	c.718C>T	p.Arg240Trp	missense_variant	5/9	1		ENSP00000461626
ITGB3	ENST00000696963.1 linkuse as main transcript	c.718C>T	p.Arg240Trp	missense_variant	5/14			ENSP00000513002		P05106-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152160

Hom.:

0

Cov.:

32

show subpopulations

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

GnomAD3 exomes

AF:

0.0000120

AC:

3

AN:

249030

Hom.:

0

AF XY:

0.0000148

AC XY:

2

AN XY:

134810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

3

AN:

1461880

Hom.:

0

Cov.:

32

AF XY:

0.00000275

AC XY:

2

AN XY:

727242

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152160

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74314

show subpopulations

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

ExAC

AF:

0.0000165

AC:

2

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Aug 20, 2024	The NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp) missense variant has been reported in at least five patients (PMID: 32200672, 7509233, 1602006, doi.org/10.2491/jjsth.10.243, and a thesis by Zapelli in 2014) with a phenotype highly specific to GT. Several probands from PMID: 32200672, PMID: 7509233, and PMID: 1602006 are homozygous (PM3) and meet the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, surface αIIbβ3 was dysfunctional as shown by defective PAC-1 and fibrinogen binding. This variant is at an extremely low frequency (below the <1/10,000 threshold) with a MAF of 0.00002196 (2/91,084 alleles) in the gnomADv4.1.0 South Asian population (PM2_supporting). It is predicted to have a deleterious effect (REVEL score 0.832; PP3) and occurs at the same residue as pathogenic variant Arg240Gln (PM5). In summary this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM5, PP3, and PP4_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The p.Arg240Trp variant in ITGB3 has been reported in 3 homozygous individuals with Glanzmann thrombasthenia (Lanza 1992 PMID: 1602006, Paciullo 2021 PMID: 32200672, Djaffar 1993 PMID: 7509233). It was also identified 0.001% (1/68038) of European chromosomes by gnomAD, v.3 (http://gnomad.broadinstitute.org). The variant is also reported in ClinVar, and has been classified as pathogenic by the ClinGen Platelet Disorders Variant Curation Expert Panel (Variation ID 13555). In vitro analysis using patient derived platelets support an impact to normal protein function. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Another variant involving this codon (p.Arg240Gln) has been identified in individuals with Glanzmann thrombasthenia and is classified as pathogenic by the ClinGen Platelet Disorders Variant Curation Expert Panel. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia. ACMG/AMP criteria applied: PM3, PM5, PS3_Supporting, PM2_Supporting, PP3, PP4. -

Glanzmann thrombasthenia 2

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2023	Variant summary: ITGB3 c.718C>T (p.Arg240Trp) results in a non-conservative amino acid change located in the Integrin beta subunit, VWA domain (IPR002369) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249030 control chromosomes (gnomAD). Another variant at the same amino acid position (p.Arg240Gln) has been classified as pathogenic in ClinVar, providing supporting evidence for R240 as a clinically significant amino acid. c.718C>T has been reported in the literature in at least one homozygous individual affected with Glanzmann Thrombasthenia 2 (example: Lanza_1992) and as a milder phenotype in heterozygous individuals, including individuals affected with isolated nonsyndromic thrombocytopenia or other clinical features of Glanzmann Thrombasthenia 2 (examples: Gueguen_2020, Lanza_1992). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, suggesting the variant causes defective ligand binding (Baker_1997), however, does not allow convincing conclusions about the variant effect. Another publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 2-4% of WT levels fibrinogen binding/platelet adhesion in a patient with a homozygous genotype. The following publications have been ascertained in the context of this evaluation (PMID: 9050889, 32757236, 1602006). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 240 of the ITGB3 protein (p.Arg240Trp). This variant is present in population databases (rs121918446, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive Glanzmann thrombasthenia (PMID: 1602006, 9215749, 32757236; Invitae). This variant is also known as p.Arg214Trp. ClinVar contains an entry for this variant (Variation ID: 13555). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ITGB3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ITGB3 function (PMID: 9050889). This variant disrupts the p.Arg240 amino acid residue in ITGB3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1371279, 9215749, 30138987). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Glanzmann thrombasthenia 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

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

-

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.39

D

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

32

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.69

D

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.14

D

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.0

M;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.74

T

PROVEAN

Uncertain

-4.2

D;.

Sift

Uncertain

0.020

D;.

Sift4G

Uncertain

0.020

D;D

Polyphen

1.0

D;.

Vest4

0.81

MutPred

0.91

Loss of disorder (P = 0.0153);Loss of disorder (P = 0.0153);

MVP

0.99

MPC

1.3

ClinPred

0.99

D

GERP RS

3.7

Varity_R

0.79

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121918446; hg19: chr17-45363729;