rs770556842
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024685.4(BBS10):c.1599_1602del(p.Thr534IlefsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L533L) has been classified as Likely benign.
Frequency
Consequence
NM_024685.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS10 | NM_024685.4 | c.1599_1602del | p.Thr534IlefsTer21 | frameshift_variant | 2/2 | ENST00000650064.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS10 | ENST00000650064.2 | c.1599_1602del | p.Thr534IlefsTer21 | frameshift_variant | 2/2 | NM_024685.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251324Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135830
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461684Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727166
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Bardet-Biedl syndrome 10 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 29, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 12, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 20, 2022 | - - |
Bardet-Biedl syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 18, 2019 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the BBS10 protein. Other variant(s) that disrupt this region (p.Tyr559*) have been determined to be pathogenic (PMID:20472660, 27788217, 28808579). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in several individuals affected with Bardet-Biedl syndrome (PMID: 20177705, 24611592, 21642631). ClinVar contains an entry for this variant (Variation ID: 188992). This variant is present in population databases (rs770556842, ExAC 0.001%). This sequence change results in a premature translational stop signal in the BBS10 gene (p.Thr534Ilefs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 190 amino acids of the BBS10 protein. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 17, 2021 | Variant summary: BBS10 c.1599_1602delAACT (p.Thr534IlefsX21) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 7.9e-06 in 251708 control chromosomes. c.1599_1602delAACT has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (example, Alvarez-Satta_2014, Chen_2011, Muller_2010). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | research | SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation | - | This variant was observed in compound heterozygosity with variant NC_000012.11:g.76741496dup - |
BBS10-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 29, 2023 | The BBS10 c.1599_1602delAACT variant is predicted to result in a frameshift and premature protein termination (p.Thr534Ilefs*21). This variant was reported in individuals with Bardet-Biedl syndrome (Muller et al. 2010. PubMed ID: 20177705; Álvarez-Satta et al. 2014. PubMed ID: 24611592; Chen et al. 2011. PubMed ID: 21642631). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in BBS10 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at