NM_024649.5:c.479G>A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_024649.5(BBS1):c.479G>A(p.Arg160Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_024649.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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BBS1 | ENST00000318312.12 | c.479G>A | p.Arg160Gln | missense_variant, splice_region_variant | Exon 5 of 17 | 1 | NM_024649.5 | ENSP00000317469.7 | ||
ENSG00000256349 | ENST00000419755.3 | c.590G>A | p.Arg197Gln | missense_variant, splice_region_variant | Exon 5 of 17 | 2 | ENSP00000398526.3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152112Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251440Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135894
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461872Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727240
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152112Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
Bardet-Biedl syndrome 1 Pathogenic:6
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Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000370228, PMID:26261414, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21520335, PS3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000028, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:4
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RNA studies demonstrate a damaging effect through aberrant splicing (PMID: 21520335); In silico analysis supports that this missense variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34426522, 34758253, 26261414, 31456290, 15770229, 21520335, 34940782, 32531858, 35886001) -
Retinitis pigmentosa Pathogenic:3
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Retinal dystrophy Pathogenic:2
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BBS1-related disorder Pathogenic:1
The BBS1 c.479G>A variant is predicted to result in the amino acid substitution p.Arg160Gln. This variant has been reported in patients with retinitis pigmentosa or milder form of Bardet-Biedl syndrome. This variant is highly prevalent in patients of Arab-Muslim origin (Sharon and Banin. 2015. PubMed ID: 26261414; Hichri et al. 2005. PubMed ID: 15770229; Schmid et al. 2011. PubMed ID: 21520335; Hjortshøj et al. 2010. PubMed ID: 20120035). RT-PCR analysis indicated that this variant results in aberrant splicing. U1snRNA -mediated therapeutic approach to correct the splice defect in patient derived cell lines significantly increased correctly spliced BBS1 transcripts, which would suggest a high potential for gene therapy (Schmid et al. 2011. PubMed ID: 21520335). This variant is reported in 0.031% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. -
Bardet-Biedl syndrome Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 160 of the BBS1 protein (p.Arg160Gln). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs376894444, gnomAD 0.03%). This missense change has been observed in individuals with Bardet-Biedl syndrome or nonsyndromic retinitis pigmentosa (PMID: 15770229, 21520335, 26261414). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 370228). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BBS1 protein function. 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