rs150743868
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_176824.3(BBS7):c.1375C>T(p.Arg459Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000309 in 1,613,486 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_176824.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BBS7 | ENST00000264499.9 | c.1375C>T | p.Arg459Cys | missense_variant | Exon 14 of 19 | 1 | NM_176824.3 | ENSP00000264499.4 | ||
BBS7 | ENST00000506636.1 | c.1375C>T | p.Arg459Cys | missense_variant | Exon 14 of 18 | 1 | ENSP00000423626.1 |
Frequencies
GnomAD3 genomes AF: 0.000296 AC: 45AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000279 AC: 70AN: 251172Hom.: 1 AF XY: 0.000339 AC XY: 46AN XY: 135740
GnomAD4 exome AF: 0.000311 AC: 454AN: 1461394Hom.: 1 Cov.: 30 AF XY: 0.000333 AC XY: 242AN XY: 727002
GnomAD4 genome AF: 0.000296 AC: 45AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27AN XY: 74296
ClinVar
Submissions by phenotype
not specified Uncertain:2
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Variant summary: BBS7 c.1375C>T (p.Arg459Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 251172 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in BBS7 causing Bardet-Biedl Syndrome (0.00028 vs 0.00062), allowing no conclusion about variant significance. c.1375C>T has been reported in the literature in one individual affected with retinitis pigmentosa. These report(s) do not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30718709). ClinVar contains an entry for this variant (Variation ID: 434498). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Bardet-Biedl syndrome 7 Uncertain:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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not provided Uncertain:2
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BBS7: PP3 -
Retinitis pigmentosa Pathogenic:1
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Inborn genetic diseases Uncertain:1
The c.1375C>T (p.R459C) alteration is located in exon 14 (coding exon 14) of the BBS7 gene. This alteration results from a C to T substitution at nucleotide position 1375, causing the arginine (R) at amino acid position 459 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
BBS7-related disorder Uncertain:1
The BBS7 c.1375C>T variant is predicted to result in the amino acid substitution p.Arg459Cys. This variant was found in the heterozygous state in an individual with retinitis pigmentosa; however, a second variant was not identified (Table S4 - Jespersgaard et al. 2019. PubMed ID: 30718709).This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD including one homozygote. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Bardet-Biedl syndrome Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 459 of the BBS7 protein (p.Arg459Cys). This variant is present in population databases (rs150743868, gnomAD 0.05%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 30718709). ClinVar contains an entry for this variant (Variation ID: 434498). 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 BBS7 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at