rs80277041
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4_StrongPM3PM4PP3PP1PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.1878G>C; p.Gln626His splicing variant has been reported in at least 5 GT probands (PMIDs: 20020534, 22513797, 25728920, 21113249, 29474205) and co-segregated in one additional affected family member (PMID:22513797). It is absent from ExAC and gnomAD. Flow cytometric studies of the mutant protein expressed in COS-7 cells showed that the mutation did not prevent expression of the GPIIb/IIIa complex on the cell surface (PMID:20020534). However, the mutation was found to result in a splice site error, skipping of exon 18, which could explain the absence of mRNA in the patients (PMID:20020534). Splicing predictors, HSF and MaxEntScan, agree that there is alteration to the WT donor site, most likely affecting splicing. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM4, PP3, PP4_Strong, and PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115852/MONDO:0010119/011
Frequency
Consequence
ENST00000262407.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ITGA2B | NM_000419.5 | c.1878G>C | p.Gln626His | missense_variant, splice_region_variant | 18/30 | ENST00000262407.6 | NP_000410.2 | |
ITGA2B | XM_011524749.2 | c.2031G>C | p.Gln677His | missense_variant, splice_region_variant | 18/29 | XP_011523051.2 | ||
ITGA2B | XM_011524750.2 | c.2031G>C | p.Gln677His | missense_variant, splice_region_variant | 18/29 | XP_011523052.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ITGA2B | ENST00000262407.6 | c.1878G>C | p.Gln626His | missense_variant, splice_region_variant | 18/30 | 1 | NM_000419.5 | ENSP00000262407 | P1 | |
ITGA2B | ENST00000648408.1 | c.1311G>C | p.Gln437His | missense_variant, splice_region_variant | 14/25 | ENSP00000498119 | ||||
ITGA2B | ENST00000592462.5 | n.673G>C | splice_region_variant, non_coding_transcript_exon_variant | 7/15 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461638Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727120
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 | Sep 04, 2020 | The c.1878G>C; p.Gln626His splicing variant has been reported in at least 5 GT probands (PMIDs: 20020534, 22513797, 25728920, 21113249, 29474205) and co-segregated in one additional affected family member (PMID: 22513797). It is absent from ExAC and gnomAD. Flow cytometric studies of the mutant protein expressed in COS-7 cells showed that the mutation did not prevent expression of the GPIIb/IIIa complex on the cell surface (PMID: 20020534). However, the mutation was found to result in a splice site error, skipping of exon 18, which could explain the absence of mRNA in the patients (PMID: 20020534). Splicing predictors, HSF and MaxEntScan, agree that there is alteration to the WT donor site, most likely affecting splicing. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM4, PP3, PP4_Strong, and PP1. - |
Glanzmann thrombasthenia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2010 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at