rs1555202806
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024685.4(BBS10):βc.39_46delβ(p.Ala14GlyfsTer79) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: not found (cov: 32)
Exomes π: 6.9e-7 ( 0 hom. )
Consequence
BBS10
NM_024685.4 frameshift
NM_024685.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.54
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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 182 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-76348312-TGCAACGCC-T is Pathogenic according to our data. Variant chr12-76348312-TGCAACGCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 521411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-76348312-TGCAACGCC-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS10 | NM_024685.4 | c.39_46del | p.Ala14GlyfsTer79 | frameshift_variant | 1/2 | ENST00000650064.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS10 | ENST00000650064.2 | c.39_46del | p.Ala14GlyfsTer79 | frameshift_variant | 1/2 | NM_024685.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457740Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 724858
GnomAD4 exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 10 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 21, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 17, 2023 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 05, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 16, 2021 | - - |
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | This sequence change creates a premature translational stop signal (p.Ala14Glyfs*79) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 710 amino acid(s) of the BBS10 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 30335236). ClinVar contains an entry for this variant (Variation ID: 521411). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the BBS10 protein in which other variant(s) (p.Cys91Leufs*5) have been determined to be pathogenic (PMID: 16582908, 20805367, 27385962). 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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Find out detailed SpliceAI scores and Pangolin per-transcript scores at