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GeneBe

rs5918

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000212.3(ITGB3):c.176T>C(p.Leu59Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,936 control chromosomes in the GnomAD database, including 16,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L59V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.13 ( 1387 hom., cov: 32)
Exomes 𝑓: 0.14 ( 15584 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

1
16

Clinical Significance

Benign reviewed by expert panel B:7O: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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0015752017).
BP6
Variant 17-47283364-T-C is Benign according to our data. Variant chr17-47283364-T-C is described in ClinVar as [Benign]. Clinvar id is 13558.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-47283364-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ITGB3NM_000212.3 linkuse as main transcriptc.176T>C p.Leu59Pro missense_variant 3/15 ENST00000559488.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ITGB3ENST00000559488.7 linkuse as main transcriptc.176T>C p.Leu59Pro missense_variant 3/151 NM_000212.3 P1P05106-1
ITGB3ENST00000571680.1 linkuse as main transcriptc.176T>C p.Leu59Pro missense_variant 3/91
ITGB3ENST00000696963.1 linkuse as main transcriptc.176T>C p.Leu59Pro missense_variant 3/14 P05106-2

Frequencies

GnomAD3 genomes
AF:
0.128
AC:
19456
AN:
152154
Hom.:
1387
Cov.:
32
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.:
34
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.:
32
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:7Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Glanzmann thrombasthenia Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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. -
Benign, reviewed by expert panelcurationClinGen Platelet Disorders Variant Curation Expert Panel, ClinGenJun 18, 2020The 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. -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalMay 31, 2017BA1, 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 submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 10, 2021This 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 providedliterature onlyOMIMJan 01, 2007- -
Myocardial infarction, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJan 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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