17-47253892-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_000212.3(ITGB3):c.31T>C(p.Trp11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,321,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
ITGB3
NM_000212.3 missense
NM_000212.3 missense
Scores
2
6
10
Clinical Significance
Conservation
PhyloP100: 0.891
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.77
PP5
?
Variant 17-47253892-T-C is Pathogenic according to our data. Variant chr17-47253892-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 953028.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGB3 | NM_000212.3 | c.31T>C | p.Trp11Arg | missense_variant | 1/15 | ENST00000559488.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGB3 | ENST00000559488.7 | c.31T>C | p.Trp11Arg | missense_variant | 1/15 | 1 | NM_000212.3 | P1 | |
ITGB3 | ENST00000571680.1 | c.31T>C | p.Trp11Arg | missense_variant | 1/9 | 1 | |||
ITGB3 | ENST00000696963.1 | c.31T>C | p.Trp11Arg | missense_variant | 1/14 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151742Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
1
AN:
151742
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.0000376 AC: 44AN: 1169378Hom.: 0 Cov.: 30 AF XY: 0.0000370 AC XY: 21AN XY: 568196
GnomAD4 exome
AF:
AC:
44
AN:
1169378
Hom.:
Cov.:
30
AF XY:
AC XY:
21
AN XY:
568196
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151742Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74152
GnomAD4 genome
?
AF:
AC:
1
AN:
151742
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74152
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Uncertain: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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
DEOGEN2
Uncertain
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
N;N;N
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.
Sift
Uncertain
D;.
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MutPred
Gain of disorder (P = 0);Gain of disorder (P = 0);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at