rs121918447
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000212.3(ITGB3):c.2332T>C(p.Ser778Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. S778S) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
ITGB3
NM_000212.3 missense
NM_000212.3 missense
Scores
9
7
2
Clinical Significance
Conservation
PhyloP100: 5.56
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.971
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGB3 | NM_000212.3 | c.2332T>C | p.Ser778Pro | missense_variant | 15/15 | ENST00000559488.7 | |
EFCAB13-DT | NR_110880.1 | n.363-6387A>G | intron_variant, non_coding_transcript_variant | ||||
EFCAB13-DT | NR_110881.1 | n.227-6387A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGB3 | ENST00000559488.7 | c.2332T>C | p.Ser778Pro | missense_variant | 15/15 | 1 | NM_000212.3 | P1 | |
EFCAB13-DT | ENST00000575039.1 | n.227-6387A>G | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Glanzmann thrombasthenia 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1992 | - - |
Glanzmann thrombasthenia Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Nov 04, 2021 | The NM_000212.2(ITGB3):c.2332T>C (p.Ser778Pro) missense variant has been reported in at one Glanzmann thrombasthenia patient (PMID: 1438206). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The receptor function of αIIbβ3, measured by functional flow cytometry, in CHO cells transiently co-transfected with the Ser778Pro variant β3 and wild type αIIb showed minimal binding to ligand mimetic antibody PAC-1 indicating that this variant impacts protein function (PMID: 8080992; PS3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PM2_supporitng. (VCEP specifications version 2; date of approval 11/04/2021). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0739);
MVP
MPC
ClinPred
D
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