chr4-122743399-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_152618.3(BBS12):c.1507G>T(p.Val503Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V503M) has been classified as Uncertain significance.
Frequency
Consequence
NM_152618.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS12 | NM_152618.3 | c.1507G>T | p.Val503Leu | missense_variant | 2/2 | ENST00000314218.8 | |
BBS12 | NM_001178007.2 | c.1507G>T | p.Val503Leu | missense_variant | 3/3 | ||
BBS12 | XM_011531680.3 | c.1507G>T | p.Val503Leu | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS12 | ENST00000314218.8 | c.1507G>T | p.Val503Leu | missense_variant | 2/2 | 1 | NM_152618.3 | P1 | |
BBS12 | ENST00000542236.5 | c.1507G>T | p.Val503Leu | missense_variant | 3/3 | 2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000994 AC: 25AN: 251448Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135898
GnomAD4 exome AF: 0.000107 AC: 156AN: 1461888Hom.: 0 Cov.: 35 AF XY: 0.000114 AC XY: 83AN XY: 727246
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74348
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2016 | The V503L variant in the BBS12 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V503L variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V503L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V503L as a variant of uncertain significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BBS12 p.V503L variant was not identified in the literature but was identified in dbSNP (ID: rs374865012) and ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was identified in control databases in 27 of 282844 chromosomes at a frequency of 0.00009546 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 4 of 25120 chromosomes (freq: 0.000159), European (non-Finnish) in 19 of 129160 chromosomes (freq: 0.000147), Other in 1 of 7220 chromosomes (freq: 0.000139), Latino in 2 of 35436 chromosomes (freq: 0.000056) and African in 1 of 24968 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.V503 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Bardet-Biedl syndrome 12 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 20, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 05, 2022 | - - |
BBS12-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 14, 2023 | The BBS12 c.1507G>T variant is predicted to result in the amino acid substitution p.Val503Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of European (Finnish) descent in gnomAD. Of note, a different variant impacting the same amino acid (p.Val503Met) has been reported in a patient with Bardet–Biedl syndrome (Patient A3227, Janssen et al. 2011. PubMed ID: 21052717). At this time, the clinical significance of the c.1507G>T (p.Val503Leu) variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2022 | The c.1507G>T (p.V503L) alteration is located in exon 2 (coding exon 1) of the BBS12 gene. This alteration results from a G to T substitution at nucleotide position 1507, causing the valine (V) at amino acid position 503 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Bardet-Biedl syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 20, 2022 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 503 of the BBS12 protein (p.Val503Leu). This variant is present in population databases (rs374865012, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BBS12-related conditions. ClinVar contains an entry for this variant (Variation ID: 389871). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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