rs537219462
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5
The NM_024685.4(BBS10):c.1250C>T(p.Ala417Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,800 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A417T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_024685.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS10 | NM_024685.4 | c.1250C>T | p.Ala417Val | missense_variant | 2/2 | ENST00000650064.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS10 | ENST00000650064.2 | c.1250C>T | p.Ala417Val | missense_variant | 2/2 | NM_024685.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461800Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727200
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2017 | - - |
Bardet-Biedl syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 29, 2022 | This variant disrupts the p.Ala417 amino acid residue in BBS10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29806606). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 417 of the BBS10 protein (p.Ala417Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Bardet-Biedl syndrome and/or inherited retinal degeneration (PMID: 21052717, 32531858). ClinVar contains an entry for this variant (Variation ID: 552931). - |
Bardet-Biedl syndrome 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 08, 2021 | NM_024685.3(BBS10):c.1250C>T(A417V) is a missense variant classified as a variant of uncertain significance in the context of Bardet-Biedl syndrome, BBS10-related. A417V has been observed in cases with relevant disease (PMID: 32531858, 21052717). Functional assessments of this variant are not available in the literature. A417V has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_024685.3(BBS10):c.1250C>T(A417V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at