rs786204444
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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):c.436C>T(p.Arg146Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000805 in 1,613,988 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
BBS1
NM_024649.5 stop_gained
NM_024649.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.79
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 11-66515543-C-T is Pathogenic according to our data. Variant chr11-66515543-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66515543-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS1 | NM_024649.5 | c.436C>T | p.Arg146Ter | stop_gained | 5/17 | ENST00000318312.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS1 | ENST00000318312.12 | c.436C>T | p.Arg146Ter | stop_gained | 5/17 | 1 | NM_024649.5 | P1 | |
ENST00000658548.1 | n.666G>A | non_coding_transcript_exon_variant | 2/2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251458Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135902
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461874Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727240
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 24, 2018 | Variant summary: BBS1 c.436C>T (p.Arg146X) 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 246238 control chromosomes (gnomAD). c.436C>T has been reported in the literature in multiple individuals affected with Bardet-Biedl Syndrome (Beales_2003, Fauser_2003, M'Hanmdi_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188752). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 12677556, 12920096, 18327255, 20177705, 21052717). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg146*) 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, no assertion criteria provided | provider interpretation | Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University | Sep 15, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Apr 08, 2014 | - - |
Bardet-Biedl syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 12, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2018 | The R146X variant in the BBS1 gene has been reported previously in the homozygous and compound heterozygous state in multiple individuals with Bardet-Biedl syndrome (M'hamdi et al., 2014; Muller et al., 2010; Leitch et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R146X variant is observed in 1/22300 (0.004%) alleles from individuals of Finnish background (Lek et al., 2016). We interpret R146X as a pathogenic variant. - |
BBS1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 29, 2023 | The BBS1 c.436C>T variant is predicted to result in premature protein termination (p.Arg146*). This variant was reported in the homozygous and compound heterozygous states in individuals with Bardet-Biedl syndrome (Beales et al. 2003. PubMed ID: 12677556; Leitch et al. 2008. PubMed ID: 18327255; Muller et al. 2010. PubMed ID: 20177705; M'hamdi et al. 2014. PubMed ID: 23432027). This variant is reported in 0.0040% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in BBS1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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