rs5918

chr17-47283364-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP2 BP4 BA1 BS3

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
• Clinical Significance: Benign reviewed by expert panel B:7 O:1
• Conservation: PhyloP100: -1.35

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB3	NM_000212.3	c.176T>C	p.Leu59Pro	missense_variant	3/15	ENST00000559488.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB3	ENST00000559488.7	c.176T>C	p.Leu59Pro	missense_variant	3/15	1	NM_000212.3	P1
ITGB3	ENST00000571680.1	c.176T>C	p.Leu59Pro	missense_variant	3/9	1
ITGB3	ENST00000696963.1	c.176T>C	p.Leu59Pro	missense_variant	3/14

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19456 AN: 152154 Hom.: 1387 Cov.: 32

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

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.: 34 AF XY: 0.140 AC XY: 101833 AN XY: 727142

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.: 32 AF XY: 0.125 AC XY: 9315 AN XY: 74446

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:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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) -

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	T
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	N
LIST_S2	Benign	0.034	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.25	T
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	T
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

Other links and lift over

dbSNP: rs5918; hg19: chr17-45360730; COSMIC: COSV71383764; COSMIC: COSV71383764;