rs587777830
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024649.5(BBS1):βc.851delβ(p.Tyr284SerfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000027 ( 0 hom. )
Consequence
BBS1
NM_024649.5 frameshift
NM_024649.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.41
Genes affected
BBS1 (HGNC:966): (Bardet-Biedl syndrome 1) Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome. The encoded protein may play a role in eye, limb, cardiac and reproductive system development. [provided by RefSeq, Jul 2008]
ZDHHC24 (HGNC:27387): (zinc finger DHHC-type containing 24) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Predicted to be involved in peptidyl-L-cysteine S-palmitoylation and protein targeting to membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-66523475-TA-T is Pathogenic according to our data. Variant chr11-66523475-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 12146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66523475-TA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS1 | NM_024649.5 | c.851del | p.Tyr284SerfsTer5 | frameshift_variant | 10/17 | ENST00000318312.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS1 | ENST00000318312.12 | c.851del | p.Tyr284SerfsTer5 | frameshift_variant | 10/17 | 1 | NM_024649.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251494Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135922
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727244
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Bardet-Biedl syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 24, 2023 | This premature translational stop signal has been observed in individual(s) with BBS1-related conditions (PMID: 12118255). ClinVar contains an entry for this variant (Variation ID: 12146). For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs587777830, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Tyr284Serfs*5) in the BBS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS1 are known to be pathogenic (PMID: 12118255, 21520335, 27032803). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 12, 2018 | Variant summary: BBS1 c.851delA (p.Tyr284SerfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 246272 control chromosomes (gnomAD). c.851delA has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Mykytyn 2002, Beales 2003, Ece Solmaz 2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
BBS1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 01, 2023 | The BBS1 c.851delA variant is predicted to result in a frameshift and premature protein termination (p.Tyr284Serfs*5). This variant has been previously reported in individuals with Bardet-Biedl syndrome (BBS) (Mykytyn et al. 2002. PubMed ID: 12118255; reported as Y284fsX288 in Table 2, Beales et al. 2003. PubMed ID: 12677556, Tables 1 and 2; Ece Solmaz et al. 2015. PubMed ID: 26518167). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-66290946-TA-T). Frameshift variants in BBS1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at