rs5918

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP2BP4BA1BS3

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:

ENSG00000259753 (HGNC:):

ENSG00000259753 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ITGB3	NM_000212.3 link	c.176T>C	p.Leu59Pro	missense_variant	Exon 3 of 15	ENST00000559488.7	NP_000203.2	P05106-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITGB3	ENST00000559488.7 link	c.176T>C	p.Leu59Pro	missense_variant	Exon 3 of 15	1	NM_000212.3	ENSP00000452786.2	P05106-1
ITGB3	ENST00000571680.1 link	c.176T>C	p.Leu59Pro	missense_variant	Exon 3 of 9	1		ENSP00000461626.1	I3L4X8
ENSG00000259753	ENST00000560629.1 link	n.140T>C		non_coding_transcript_exon_variant	Exon 3 of 18	2		ENSP00000456711.2	H3BM21
ITGB3	ENST00000696963.1 link	c.176T>C	p.Leu59Pro	missense_variant	Exon 3 of 14			ENSP00000513002.1	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

GnomAD2 exomes

AF:

0.121

AC:

30400

AN:

251122

AF XY:

0.123

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 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

AC:

3612

AN:

33478

Gnomad4 AMR exome

AF:

0.0797

AC:

3564

AN:

44722

Gnomad4 ASJ exome

AF:

0.155

AC:

4052

AN:

26130

Gnomad4 EAS exome

AF:

0.00338

AC:

134

AN:

39700

Gnomad4 SAS exome

AF:

0.0962

AC:

8296

AN:

86252

Gnomad4 FIN exome

AF:

0.144

AC:

7712

AN:

53400

Gnomad4 NFE exome

AF:

0.153

AC:

169759

AN:

1111820

Gnomad4 Remaining exome

AF:

0.133

AC:

8049

AN:

60394

Heterozygous variant carriers

10317

20633

30950

41266

51583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

5888

11776

17664

23552

29440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

0.105253

AN:

0.105253

Gnomad4 AMR

AF:

0.102

AC:

0.102313

AN:

0.102313

Gnomad4 ASJ

AF:

0.144

AC:

0.143599

AN:

0.143599

Gnomad4 EAS

AF:

0.00674

AC:

0.00673854

AN:

0.00673854

Gnomad4 SAS

AF:

0.0990

AC:

0.0990468

AN:

0.0990468

Gnomad4 FIN

AF:

0.133

AC:

0.133296

AN:

0.133296

Gnomad4 NFE

AF:

0.156

AC:

0.156125

AN:

0.156125

Gnomad4 OTH

AF:

0.141

AC:

0.140758

AN:

0.140758

Heterozygous variant carriers

875

1750

2625

3500

4375

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.144

Hom.:

7301

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

Jun 10, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 31, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glanzmann thrombasthenia

Benign:2

Jun 18, 2020

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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. -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PL(A1)/(A2) ALLOANTIGEN POLYMORPHISM

Benign:1

Jan 01, 2007

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Myocardial infarction, susceptibility to

Other:1

Jan 01, 2007

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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;.

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

Mutation Taster

=94/6

polymorphism (auto)

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