17-47283379-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PS3_SupportingPP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The ITGB3 missense variant NM_000212.3:c.191G>A replaces the cysteine residue with a tyrosine residue (p.Cys64Tyr). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-21 in PMID:20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and a second ITGB3 variant was not identified. The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-15% compared to wild type; PMID:20020534; PS3_supporting). The variant is also absent from control population databases including gnomADv4.1.0 (PM2_supporting) and predicted by in silico tools to be damaging to protein function (REVEL score for this variant is 0.981; PP3). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA291224490/MONDO:0100326/011

Frequency

Genomes: not found (cov: 32)

Consequence

ITGB3
NM_000212.3 missense

Scores

14
3
1

Clinical Significance

Uncertain significance reviewed by expert panel U:1

Conservation

PhyloP100: 10.0
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 Uncertain_significance. Variant got 3 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITGB3NM_000212.3 linkc.191G>A p.Cys64Tyr missense_variant Exon 3 of 15 ENST00000559488.7 NP_000203.2 P05106-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITGB3ENST00000559488.7 linkc.191G>A p.Cys64Tyr missense_variant Exon 3 of 15 1 NM_000212.3 ENSP00000452786.2 P05106-1
ITGB3ENST00000571680.1 linkc.191G>A p.Cys64Tyr missense_variant Exon 3 of 9 1 ENSP00000461626.1 I3L4X8
ENSG00000259753ENST00000560629.1 linkn.155G>A non_coding_transcript_exon_variant Exon 3 of 18 2 ENSP00000456711.2 H3BM21
ITGB3ENST00000696963.1 linkc.191G>A p.Cys64Tyr missense_variant Exon 3 of 14 ENSP00000513002.1 P05106-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Glanzmann thrombasthenia Uncertain:1
Uncertain significance, reviewed by expert panelcurationClinGen Platelet Disorders Variant Curation Expert Panel, ClinGenAug 20, 2024The ITGB3 missense variant NM_000212.3:c.191G>A replaces the cysteine residue with a tyrosine residue (p.Cys64Tyr). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-21 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and a second ITGB3 variant was not identified. The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-15% compared to wild type; PMID: 20020534; PS3_supporting). The variant is also absent from control population databases including gnomADv4.1.0 (PM2_supporting) and predicted by in silico tools to be damaging to protein function (REVEL score for this variant is 0.981; PP3). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.60
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
H;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-10
D;.
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.98
MutPred
0.98
Loss of disorder (P = 0.0736);Loss of disorder (P = 0.0736);
MVP
0.98
MPC
1.6
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.97
gMVP
0.99

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: rs74554539; hg19: chr17-45360745; API