chr17-47253892-T-C

Position:

chr17-47253892-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_SupportingPS3PM3PP4_Strong

This summary comes from the ClinGen Evidence Repository: The c.31T>C (p.Trp11Arg) missense variant has been reported in at least 3 probands (PMIDs: 25728920, 28748566, 25373348), at least one of whom (PMID:25728920) meets criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. Two homozygotes (PM3) and one compound heterozygote (with Likely Pathogenic Cys486Trp variant) has been observed. It is absent from controls in gnomADv2.1.1 (PM2_supporting. The expression of αIIbβ3 on the surface of HEK cells was evaluated by flow cytometry and showed no detectable αlIbβ3 protein (PMID:36122578; PS3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PS3, PM2_supporting, PM3, and PP4_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA291240306/MONDO:0010119/011

Frequency

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

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:2U:1

Conservation

PhyloP100: 0.891

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 Pathogenic. Variant got 11 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.

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.31T>C	p.Trp11Arg	missense_variant	1/15	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.31T>C	p.Trp11Arg	missense_variant	1/15	1	NM_000212.3	ENSP00000452786	P1	P05106-1
ITGB3	ENST00000571680.1 linkuse as main transcript	c.31T>C	p.Trp11Arg	missense_variant	1/9	1		ENSP00000461626
ITGB3	ENST00000696963.1 linkuse as main transcript	c.31T>C	p.Trp11Arg	missense_variant	1/14			ENSP00000513002		P05106-2

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151742

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1169378

Hom.:

Cov.:

AF XY:

0.0000370

AC XY:

AN XY:

568196

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000456

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151742

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74152

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Nov 02, 2023

The c.31T>C (p.Trp11Arg) missense variant has been reported in at least 3 probands (PMIDs: 25728920, 28748566, 25373348), at least one of whom (PMID: 25728920) meets criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. Two homozygotes (PM3) and one compound heterozygote (with Likely Pathogenic Cys486Trp variant) has been observed. It is absent from controls in gnomADv2.1.1 (PM2_supporting. The expression of αIIbβ3 on the surface of HEK cells was evaluated by flow cytometry and showed no detectable αlIbβ3 protein (PMID: 36122578; PS3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PS3, PM2_supporting, PM3, and PP4_strong. -

Glanzmann thrombasthenia 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 12, 2024

Variant summary: ITGB3 c.31T>C (p.Trp11Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.31T>C has been reported in the literature in individuals affected with Glanzmann Thrombasthenia 2 (Sandrock-Lang_2015, Nurden_2015, Waxman_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function shows that the variant does not affect protein biosynthesis, but affects the transport of the protein to the membrane (Waxman_2022). The following publications have been ascertained in the context of this evaluation (PMID: 25728920, 36122578, 25373348, 27469266). ClinVar contains an entry for this variant (Variation ID: 953028). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 11 of the ITGB3 protein (p.Trp11Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ITGB3 -related bleeding disorders (PMID: 25373348, 25728920). ClinVar contains an entry for this variant (Variation ID: 953028). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Uncertain

0.47

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.30

T;T

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.97

N;.

Sift

Uncertain

0.011

D;.

Sift4G

Benign

0.28

T;T

Polyphen

0.44

B;.

Vest4

0.65

MutPred

0.70

Gain of disorder (P = 0);Gain of disorder (P = 0);

MVP

0.90

MPC

0.90

ClinPred

0.23

GERP RS

2.3

Varity_R

0.31

gMVP

0.81

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over