rs138036823
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_152618.3(BBS12):āc.116T>Cā(p.Ile39Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00729 in 1,613,476 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0057 ( 2 hom., cov: 33)
Exomes š: 0.0075 ( 53 hom. )
Consequence
BBS12
NM_152618.3 missense
NM_152618.3 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 7.05
Genes affected
BBS12 (HGNC:26648): (Bardet-Biedl syndrome 12) The protein encoded by this gene is part of a complex that is involved in membrane trafficking. The encoded protein is a molecular chaperone that aids in protein folding upon ATP hydrolysis. This protein also plays a role in adipocyte differentiation. Defects in this gene are a cause of Bardet-Biedl syndrome type 12. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.009558558).
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00568 (865/152324) while in subpopulation AMR AF= 0.0114 (175/15294). AF 95% confidence interval is 0.0101. There are 2 homozygotes in gnomad4. There are 387 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS12 | NM_152618.3 | c.116T>C | p.Ile39Thr | missense_variant | 2/2 | ENST00000314218.8 | |
BBS12 | NM_001178007.2 | c.116T>C | p.Ile39Thr | missense_variant | 3/3 | ||
BBS12 | XM_011531680.3 | c.116T>C | p.Ile39Thr | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS12 | ENST00000314218.8 | c.116T>C | p.Ile39Thr | missense_variant | 2/2 | 1 | NM_152618.3 | P1 | |
BBS12 | ENST00000542236.5 | c.116T>C | p.Ile39Thr | missense_variant | 3/3 | 2 | P1 | ||
BBS12 | ENST00000433287.1 | c.116T>C | p.Ile39Thr | missense_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00568 AC: 865AN: 152206Hom.: 2 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00631 AC: 1584AN: 251186Hom.: 6 AF XY: 0.00689 AC XY: 935AN XY: 135752
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GnomAD4 exome AF: 0.00746 AC: 10893AN: 1461152Hom.: 53 Cov.: 31 AF XY: 0.00758 AC XY: 5511AN XY: 726770
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GnomAD4 genome ? AF: 0.00568 AC: 865AN: 152324Hom.: 2 Cov.: 33 AF XY: 0.00520 AC XY: 387AN XY: 74490
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ExAC
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 20, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 22, 2022 | Variant summary: BBS12 c.116T>C (p.Ile39Thr) 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 0.0063 in 251186 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS12 causing Bardet-Biedl Syndrome phenotype (0.00076), strongly suggesting that the variant is benign. c.116T>C has been reported in the literature in individuals affected with Bardet-Biedl Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. At-least one co-occurrence with other pathogenic variant(s) have been reported (BBS12 c.814C>T, p.Arg272*), providing supporting evidence for a benign role (example, Manara_2019). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Zaghoul_2010). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 04, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Bardet-Biedl syndrome 12 Uncertain:2Benign:2
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 13, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Bardet-Biedl syndrome 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Dec 22, 2014 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Apr 19, 2017 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 09, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | BBS12: BS2 - |
Bardet-Biedl syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at