rs119466001
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_176824.3(BBS7):c.968A>G(p.His323Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000583 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
BBS7
NM_176824.3 missense
NM_176824.3 missense
Scores
2
6
11
Clinical Significance
Conservation
PhyloP100: 6.84
Genes affected
BBS7 (HGNC:18758): (Bardet-Biedl syndrome 7) This gene encodes one of eight proteins that form the BBSome complex containing BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10. The BBSome complex is believed to recruit Rab8(GTP) to the primary cilium and promote ciliogenesis. The BBSome complex assembly is mediated by a complex composed of three chaperonin-like BBS proteins (BBS6, BBS10, and BBS12) and CCT/TRiC family chaperonins. Mutations in this gene are implicated in Bardet-Biedl syndrome, a genetic disorder whose symptoms include obesity, retinal degeneration, polydactyly and nephropathy; however, mutations in this gene and the BBS8 gene are thought to play a minor role and mutations in chaperonin-like BBS genes are found to be a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population. Two transcript variants encoding distinct isoforms have been identified for this gene.[provided by RefSeq, Oct 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-121847473-T-C is Pathogenic according to our data. Variant chr4-121847473-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-121847473-T-C is described in Lovd as [Likely_pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.20648062).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS7 | NM_176824.3 | c.968A>G | p.His323Arg | missense_variant | 10/19 | ENST00000264499.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS7 | ENST00000264499.9 | c.968A>G | p.His323Arg | missense_variant | 10/19 | 1 | NM_176824.3 | P1 | |
BBS7 | ENST00000506636.1 | c.968A>G | p.His323Arg | missense_variant | 10/18 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152236Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251292Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135820
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GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461420Hom.: 0 Cov.: 30 AF XY: 0.0000426 AC XY: 31AN XY: 727038
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GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74374
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 15, 2020 | Published functional studies demonstrate H323R impacts the rate of BBS7 nuclear export through a dominant negative mechanism (Zaghloul et al., 2010; Gascue et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12567324, 20498079, 31589614, 22302990) - |
Bardet-Biedl syndrome 7 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2003 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 30, 2023 | - - |
BBS7-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 24, 2024 | The BBS7 c.968A>G variant is predicted to result in the amino acid substitution p.His323Arg. This variant has been found in the homozygous state in three individuals with Bardet-Biedl syndrome from two families (Badano et al. 2003. PubMed ID: 12567324). Functional studies indicate this variant disrupts BBS7 function (Zaghloul et al. 2010. PubMed ID: 20498079; Gascue et al. 2012. PubMed ID: 22302990). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. - |
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 323 of the BBS7 protein (p.His323Arg). This variant is present in population databases (rs119466001, gnomAD 0.008%). This missense change has been observed in individuals with Bardet-Biedl syndrome (PMID: 12567324, 32531858). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3015). 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 not expected to disrupt BBS7 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects BBS7 function (PMID: 20498079, 22302990). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at