rs758522600
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024685.4(BBS10):c.959_962del(p.Ser320IlefsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000372 in 1,612,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BBS10
NM_024685.4 frameshift
NM_024685.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.03
Genes affected
BBS10 (HGNC:26291): (Bardet-Biedl syndrome 10) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by progressive retinal degeneration, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse and the similar phenotypes exhibited by mutations in BBS gene family members is likely due to their shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene is likely not a ciliary protein but rather has distant sequence homology to type II chaperonins. As a molecular chaperone, this protein may affect the folding or stability of other ciliary or basal body proteins. Inhibition of this protein's expression impairs ciliogenesis in preadipocytes. Mutations in this gene cause Bardet-Biedl syndrome type 10. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 80 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-76347022-ATAAC-A is Pathogenic according to our data. Variant chr12-76347022-ATAAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 266102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-76347022-ATAAC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS10 | NM_024685.4 | c.959_962del | p.Ser320IlefsTer5 | frameshift_variant | 2/2 | ENST00000650064.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS10 | ENST00000650064.2 | c.959_962del | p.Ser320IlefsTer5 | frameshift_variant | 2/2 | NM_024685.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152234Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250208Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135402
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460500Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726648
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74376
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 10 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 06, 2018 | - - |
Likely pathogenic, no assertion criteria provided | curation | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Apr 02, 2015 | - - |
Asphyxiating thoracic dystrophy 3 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre | - | - - |
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Ser320Ilefs*5) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 404 amino acid(s) of the BBS10 protein. This variant is present in population databases (rs758522600, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with clinical features of BBS10-related conditions (PMID: 27894351). ClinVar contains an entry for this variant (Variation ID: 266102). This variant disrupts a region of the BBS10 protein in which other variant(s) (p.Val707*) have been determined to be pathogenic (PMID: 20472660, 22773737, 25982971, 27486776). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at