rs121918445
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000212.3(ITGB3):c.433G>A(p.Asp145Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D145Y) has been classified as Pathogenic.
Frequency
Consequence
NM_000212.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGB3 | NM_000212.3 | c.433G>A | p.Asp145Asn | missense_variant | 4/15 | ENST00000559488.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGB3 | ENST00000559488.7 | c.433G>A | p.Asp145Asn | missense_variant | 4/15 | 1 | NM_000212.3 | P1 | |
ITGB3 | ENST00000571680.1 | c.433G>A | p.Asp145Asn | missense_variant | 4/9 | 1 | |||
ITGB3 | ENST00000696963.1 | c.433G>A | p.Asp145Asn | missense_variant | 4/14 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Glanzmann thrombasthenia Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Nov 02, 2023 | The NM_000212.2:c.433G>A variant that results in the Asp145Asn amino acid change is reported in two homozygous individuals in the literature (PMID: 31064749 and Proband NR in PMID: 9215749, Blood abstracts 1997 Suppl., & GT database; PM3). An additional homozygous patient has been identified through clinical testing. One published proband (Ward et al., 1997 Blood Abstracts, Vol 90, Suppl. & GT database, MCW), an Arab female (NR) with frequent bruising, gingival bleeding, epistaxis, menorrhagia, requiring >2 platelet transfusions, showed absent platelet aggregation with collagen, arachidonic acid, thrombin, ADP and normal aggregation with ristocetin (PP4_moderate). It is absent in population databases, including gnomADv2.1.1 (PM2_supporting) and is predicted damaging by in-silico tools (REVEL score 0.89; PP3). Asp145Tyr is a variant reported at the same residue and classified as likely pathogenic by the Platelet Disorders VCEP (PM5). In summary, based on the available evidence at this time, the Asp145Asn variant is classified as Likely Pathogenic. GT-specific criteria applied: PM2_supporting, PM3, PP3, PP4_moderate and PM5. - |
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at