rs5918

Positions:

chr17-47283364-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BS3BP2BP4BA1

This summary comes from the ClinGen Evidence Repository: The ITGB3 c.176T>C (p.Leu59Pro) missense variant has been reported many times in the literature as an alloantigenic site. This variant has been observed in cis with several other Glanzmann thrombasthenia variants, including the pathogenic c.224del frameshift variant (PMID:25728920). It is present in gnomAD at an overall allele frequency of 0.1223 (and 0.1550 in the non-Finnish European population). Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.217. Functional studies in CHO cells have shown no deleterious effect on surface expression or fibrinogen binding (PMID:10727448). In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1, BS3, BP2, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA123235/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.13 ( 1387 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15584 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8O:1

Conservation

PhyloP100: -1.35

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 Benign. Variant got -14 ACMG points.

BP2

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

BP4

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

BS3

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

BA1

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.176T>C	p.Leu59Pro	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.176T>C	p.Leu59Pro	missense_variant	3/15	1	NM_000212.3	ENSP00000452786	P1	P05106-1
ITGB3	ENST00000571680.1 linkuse as main transcript	c.176T>C	p.Leu59Pro	missense_variant	3/9	1		ENSP00000461626
ITGB3	ENST00000696963.1 linkuse as main transcript	c.176T>C	p.Leu59Pro	missense_variant	3/14			ENSP00000513002		P05106-2

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19456

AN:

152154

Hom.:

1387

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.149

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.144

Gnomad EAS

AF:

0.00634

Gnomad SAS

AF:

0.0998

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.156

Gnomad OTH

AF:

0.142

GnomAD3 exomes

AF:

0.121

AC:

30400

AN:

251122

Hom.:

2106

AF XY:

0.123

AC XY:

16665

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.106

Gnomad AMR exome

AF:

0.0767

Gnomad ASJ exome

AF:

0.157

Gnomad EAS exome

AF:

0.00277

Gnomad SAS exome

AF:

0.0970

Gnomad FIN exome

AF:

0.145

Gnomad NFE exome

AF:

0.154

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.141

AC:

206046

AN:

1461664

Hom.:

15584

Cov.:

AF XY:

0.140

AC XY:

101833

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.108

Gnomad4 AMR exome

AF:

0.0797

Gnomad4 ASJ exome

AF:

0.155

Gnomad4 EAS exome

AF:

0.00338

Gnomad4 SAS exome

AF:

0.0962

Gnomad4 FIN exome

AF:

0.144

Gnomad4 NFE exome

AF:

0.153

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.128

AC:

19457

AN:

152272

Hom.:

1387

Cov.:

AF XY:

0.125

AC XY:

9315

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.105

Gnomad4 AMR

AF:

0.102

Gnomad4 ASJ

AF:

0.144

Gnomad4 EAS

AF:

0.00674

Gnomad4 SAS

AF:

0.0990

Gnomad4 FIN

AF:

0.133

Gnomad4 NFE

AF:

0.156

Gnomad4 OTH

AF:

0.141

Alfa

AF:

0.147

Hom.:

3696

Bravo

AF:

0.124

TwinsUK

AF:

0.157

AC:

583

ALSPAC

AF:

0.150

AC:

580

ESP6500AA

AF:

0.107

AC:

470

ESP6500EA

AF:

0.152

AC:

1305

ExAC

AF:

0.123

AC:

14952

Asia WGS

AF:

0.0640

AC:

225

AN:

3478

EpiCase

AF:

0.152

EpiControl

AF:

0.161

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	This variant is associated with the following publications: (PMID: 29462793, 29965811, 29038237, 29117201, 11723016, 2565345, 18657307, 22133274, 23155369, 20472470, 10727448, 15826939, 11028489, 24720773, 21919778, 21109038, 21813062, 19245802, 19388931, 18214290, 15609125, 19530321, 10195947, 21353223, 18836720, 21241403) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Glanzmann thrombasthenia

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Jun 18, 2020	The ITGB3 c.176T>C (p.Leu59Pro) missense variant has been reported many times in the literature as an alloantigenic site. This variant has been observed in cis with several other Glanzmann thrombasthenia variants, including the pathogenic c.224del frameshift variant (PMID: 25728920). It is present in gnomAD at an overall allele frequency of 0.1223 (and 0.1550 in the non-Finnish European population). Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.217. Functional studies in CHO cells have shown no deleterious effect on surface expression or fibrinogen binding (PMID: 10727448). In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1, BS3, BP2, BP4. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	May 31, 2017	BA1, BP4, BP6; This alteration has an allele frequency that is greater than 5% healthy populations (ExAC/gnomAD), is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

PL(A1)/(A2) ALLOANTIGEN POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Myocardial infarction, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

1.1

DANN

Benign

0.42

DEOGEN2

Uncertain

0.47

T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.034

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.20

N;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

0.63

N;.

Sift

Benign

0.32

T;.

Sift4G

Benign

0.27

T;T

Polyphen

0.0030

B;.

Vest4

0.073

MPC

0.66

ClinPred

0.015

GERP RS

-12

Varity_R

0.15

gMVP

0.80

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