rs202205304
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_024649.5(BBS1):c.1535G>A(p.Arg512His) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,614,186 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R512C) has been classified as Uncertain significance.
Frequency
Consequence
NM_024649.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS1 | NM_024649.5 | c.1535G>A | p.Arg512His | missense_variant | 15/17 | ENST00000318312.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS1 | ENST00000318312.12 | c.1535G>A | p.Arg512His | missense_variant | 15/17 | 1 | NM_024649.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251494Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135920
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26AN XY: 727244
GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74460
ClinVar
Submissions by phenotype
Bardet-Biedl syndrome 1 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 13, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 02, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 18, 2018 | The p.Arg512His variant in BBS1 has been reported in the heterozygous state in 1 individual with Bardet-Biedl syndrome (BBS) who also carried 2 other reportedly damaging alleles in another gene known to cause BBS (Chen 2011). This variant h as also been reported in ClinVar (Variation ID: 225300). This variant has been i dentified in 0.01% (13/126704) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202205304). Althoug h this variant has been seen in the general population, its frequency is low eno ugh to be consistent with a recessive carrier frequency. Computational predictio n tools and conservation analysis suggest that the ${MatchVariant_1_AminoAcidCha nge} variant may not impact the protein, though this information is not predicti ve enough to rule out pathogenicity. In summary, the clinical significance of th is variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 19, 2022 | Variant summary: BBS1 c.1535G>A (p.Arg512His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251494 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BBS1 causing Bardet-Biedl Syndrome (6.4e-05 vs 0.0015), allowing no conclusion about variant significance. c.1535G>A has been reported in the literature in at least one heterozygous individual affected with Bardet-Biedl Syndrome, however in this case the individual also had compound heterozygous variants in BBS12 which may explain the phenotype (e.g. Chen_2011). Therefore, this report does not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. The variant was found to have no impact on the interaction between BBS1 and BBS9 in a yeast two hybrid model system (e.g. Woodsmith_2017). However, to our knowledge, no other experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
BBS1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 20, 2023 | The BBS1 c.1535G>A variant is predicted to result in the amino acid substitution p.Arg512His. This variant has been reported in the heterozygous state in a Bardet-Biedl syndrome family; however, two heterozygous variants were also identified in BBS12 (Chen et al. 2011. PubMed ID: 21642631). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-66298426-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Bardet-Biedl syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 512 of the BBS1 protein (p.Arg512His). This variant is present in population databases (rs202205304, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BBS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 225300). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at