rs1057518837
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000212.3(ITGB3):c.1699C>T(p.Gln567Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,626 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. Q567Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000212.3 stop_gained
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.1699C>T | p.Gln567Ter | stop_gained | 11/15 | ENST00000559488.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGB3 | ENST00000559488.7 | c.1699C>T | p.Gln567Ter | stop_gained | 11/15 | 1 | NM_000212.3 | P1 | |
ITGB3 | ENST00000696963.1 | c.1699C>T | p.Gln567Ter | stop_gained | 11/14 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461626Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727130
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Glanzmann thrombasthenia Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Apr 06, 2023 | The c.1699C>T (p.Gln567Ter) variant in exon 11 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 11/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Glanzmann Patient, "HEMOSTAZA SKOZI KLINIČNE PRIMERE", August 2022) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0% (<25%), as measured by flow cytometry (PP4_moderate). This individual is compound heterozygous for this variant and likely pathogenic variant c.749A>G (p.Asp250Gly). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate and PM2_Supporting (VCEP specifications version 2). - |
Prolonged bleeding time;C1458140:Abnormal bleeding Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 06, 2015 | - - |
Platelet-type bleeding disorder 16 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at