17-47283375-C-T

Position:

chr17-47283375-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM3_SupportingPP4_StrongPP3PM2_SupportingPS3_Moderate

This summary comes from the ClinGen Evidence Repository: The missense variant, NM_000212.3(ITGB3):c.187C>T (p.Arg63Cys), has been reported in one compound heterozygous proband (PMID:25728920) with Pathogenic variant NM_000212.2:c.505C>T Arg169Ter (PM3_supporting). The patient (GT7 in PMID:25728920/Case 2 in PMID:35286390) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 15% (<25%), as measured by flow cytometry (PP4_strong). It occurs at an extremely low frequency, with an overall allele frequency in gnomAD of 0.00002476 (MAF of 0.00005012 in the East Asian population; PM2_supporting). It is predicted damaging by in-silico tools (REVEL score of 0.98; PP3). In transiently transfected COS‐7 cells expressing Arg63Cys mutant integrin FACS analysis showed 85% reduction of αIIbβ3Cys63 expression (PS3_moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PP3, PS3_moderate (VCEP specifications version 2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8622892/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ITGB3
ENST00000559488.7 missense

Scores

15

2

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:1U:2

Conservation

PhyloP100: 7.71

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS3

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

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.

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.187C>T	p.Arg63Cys	missense_variant	3/15	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.187C>T	p.Arg63Cys	missense_variant	3/15	1	NM_000212.3	ENSP00000452786	P1	P05106-1
ITGB3	ENST00000571680.1 linkuse as main transcript	c.187C>T	p.Arg63Cys	missense_variant	3/9	1		ENSP00000461626
ITGB3	ENST00000696963.1 linkuse as main transcript	c.187C>T	p.Arg63Cys	missense_variant	3/14			ENSP00000513002		P05106-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

3

AN:

152230

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

5

AN:

251276

Hom.:

0

AF XY:

0.0000221

AC XY:

3

AN XY:

135814

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

43

AN:

1461882

Hom.:

0

Cov.:

33

AF XY:

0.0000330

AC XY:

24

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

3

AN:

152230

Hom.:

0

Cov.:

32

AF XY:

0.0000269

AC XY:

2

AN XY:

74376

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

0

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

4

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Pathogenic:1Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Aug 15, 2023	The missense variant, NM_000212.3(ITGB3):c.187C>T (p.Arg63Cys), has been reported in one compound heterozygous proband (PMID: 25728920) with Pathogenic variant NM_000212.2:c.505C>T Arg169Ter (PM3_supporting). The patient (GT7 in PMID: 25728920/Case 2 in PMID: 35286390) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 15% (<25%), as measured by flow cytometry (PP4_strong). It occurs at an extremely low frequency, with an overall allele frequency in gnomAD of 0.00002476 (MAF of 0.00005012 in the East Asian population; PM2_supporting). It is predicted damaging by in-silico tools (REVEL score of 0.98; PP3). In transiently transfected COS‐7 cells expressing Arg63Cys mutant integrin FACS analysis showed 85% reduction of αIIbβ3Cys63 expression (PS3_moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PP3, PS3_moderate (VCEP specifications version 2). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ITGB3 c.187C>T (p.Arg63Cys) variant has been reported in one study and was found in a compound heterozygous state with a nonsense variant in one patient with Glanzmann thrombasthenia, type II (Nurden et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. When the p.Arg63Cys-containing integrin was transiently expressed in COS-7 cells, Î±IIbÎ²3 protein expression was reduced by 85% compared to wild type. Immunoblotting of lysed cells from the patient also showed that pro-Î±IIb and mature Î±IIb expression was reduced, indicating that Î±IIbÎ²3 complex maturation was slowed or impaired. Based on the evidence, the p.Arg63Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for thrombasthenia of Glanzmann and Naegeli. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 08, 2024

Variant summary: ITGB3 c.187C>T (p.Arg63Cys) results in a non-conservative amino acid change located in the PSI domain (IPR016201) 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 2e-05 in 251276 control chromosomes. c.187C>T has been reported in the literature in the compound heterozygous state in at least one individual affected with Glanzmann Thrombasthenia 2 (Nurden_2015). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 15% of normal activity (Nurden_2015). The following publication have been ascertained in the context of this evaluation (PMID: 25728920). ClinVar contains an entry for this variant (Variation ID: 631774). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.44

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

31

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

1.0

D

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.62

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.9

H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.54

T

PROVEAN

Pathogenic

-6.8

D;.

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.91

Gain of catalytic residue at P62 (P = 0.0074);Gain of catalytic residue at P62 (P = 0.0074);

MVP

0.99

MPC

1.5

ClinPred

1.0

D

GERP RS

5.9

Varity_R

0.79

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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: rs199866795; hg19: chr17-45360741; COSMIC: COSV71383286; COSMIC: COSV71383286;