rs758972393
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001174150.2(ARL13B):āc.461A>Gā(p.Asn154Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000623 in 1,604,522 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).
Frequency
Consequence
NM_001174150.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000264 AC: 4AN: 151708Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000818 AC: 2AN: 244580Hom.: 0 AF XY: 0.00000758 AC XY: 1AN XY: 131850
GnomAD4 exome AF: 0.00000413 AC: 6AN: 1452814Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2AN XY: 722242
GnomAD4 genome AF: 0.0000264 AC: 4AN: 151708Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74112
ClinVar
Submissions by phenotype
Joubert syndrome 8 Pathogenic:2
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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARL13B protein function. ClinVar contains an entry for this variant (Variation ID: 217552). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869). This variant is present in population databases (rs758972393, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 154 of the ARL13B protein (p.Asn154Ser). -
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not specified Uncertain:1
Variant summary: ARL13B c.461A>G (p.Asn154Ser) results in a 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 8.2e-06 in 244580 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.461A>G has been reported in the literature in at least one compound heterozygous individual affected with Joubert Syndrome (e.g.Bachmann-Gagescu_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at