rs200116631
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_024649.5(BBS1):c.1339G>A(p.Ala447Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000242 in 1,614,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A447A) has been classified as Likely benign.
Frequency
Consequence
NM_024649.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS1 | NM_024649.5 | c.1339G>A | p.Ala447Thr | missense_variant, splice_region_variant | 13/17 | ENST00000318312.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS1 | ENST00000318312.12 | c.1339G>A | p.Ala447Thr | missense_variant, splice_region_variant | 13/17 | 1 | NM_024649.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250660Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135594
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727246
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74476
ClinVar
Submissions by phenotype
Bardet-Biedl syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 30, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 08, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 07, 2023 | The BBS1 c.1339G>A variant is classified as Likely Pathogenic (PS3, PM2_Supporting, PM3) The BBS1 c.1339G>A variant is a single nucleotide change in exon 13/17 of the BBS1 gene, which is predicted to change the amino acid alanine at position 447 in the protein to threonine. This variant is located in the donor splice region of exon 13. The variant is rare in population databases (gnomAD allele frequency = 0.0045%; 7 het and 0 hom in 152206 sequenced alleles; highest frequency = 0.020%, South Asian population) (PM2_Supporting). An RT-PCR study has been published which demonstrated an extra 115bp originating from intron 13 cut into cDNA, which generated a predicted premature termination codon (PTC) in the BBS1 protein. Further expression analysis by using real-time reverse-transcribed PCR confirmed the occurrence of nonsense-mediated decay (Yan et al, 2022 PMID:35692835) (PS3). This variant has been detected in a homozygous state in this patient, and in at least 3 other probands reported in the literature with polydactyl (PMID:33594065; PMID:28341476; PMID:32349990) (PM3). The variant has been reported in dbSNP (rs200116631) and in the HGMD database: CM178896. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 531824). - |
not provided Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare | Dec 24, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2023 | Non-canonical splice site variant demonstrated to result in loss of function (Yan K, 2022); This variant is associated with the following publications: (PMID: 34426522, 28341476, 32349990, 33594065, 35692835) - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2018 | - - |
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 447 of the BBS1 protein (p.Ala447Thr). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (rs200116631, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of Bardet-Biedl syndrome (PMID: 28341476, 32349990, 33594065; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 531824). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at