chr11-66515586-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_024649.5(BBS1):​c.479G>A​(p.Arg160Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

BBS1
NM_024649.5 missense, splice_region

Scores

6
7
6
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 8.03
Variant links:
Genes affected
BBS1 (HGNC:966): (Bardet-Biedl syndrome 1) Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome. The encoded protein may play a role in eye, limb, cardiac and reproductive system development. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-66515586-G-A is Pathogenic according to our data. Variant chr11-66515586-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66515586-G-A is described in Lovd as [Pathogenic]. Variant chr11-66515586-G-A is described in Lovd as [Pathogenic]. Variant chr11-66515586-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BBS1NM_024649.5 linkc.479G>A p.Arg160Gln missense_variant, splice_region_variant Exon 5 of 17 ENST00000318312.12 NP_078925.3 Q8NFJ9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BBS1ENST00000318312.12 linkc.479G>A p.Arg160Gln missense_variant, splice_region_variant Exon 5 of 17 1 NM_024649.5 ENSP00000317469.7 Q8NFJ9-1
ENSG00000256349ENST00000419755.3 linkc.590G>A p.Arg197Gln missense_variant, splice_region_variant Exon 5 of 17 2 ENSP00000398526.3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152112
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251440
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461872
Hom.:
0
Cov.:
33
AF XY:
0.00000825
AC XY:
6
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152112
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1 Pathogenic:6
Dec 05, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 10, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genomics England Pilot Project, Genomics England
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 23, 2015
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 03, 2022
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000370228, PMID:26261414, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21520335, PS3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000028, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 12, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:4
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 14, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

RNA studies demonstrate a damaging effect through aberrant splicing (PMID: 21520335); In silico analysis supports that this missense variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34426522, 34758253, 26261414, 31456290, 15770229, 21520335, 34940782, 32531858, 35886001) -

Retinitis pigmentosa Pathogenic:3
Jun 23, 2019
Sharon lab, Hadassah-Hebrew University Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Dec 20, 2022
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:2
Apr 01, 2019
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2012
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

BBS1-related disorder Pathogenic:1
Aug 06, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The BBS1 c.479G>A variant is predicted to result in the amino acid substitution p.Arg160Gln. This variant has been reported in patients with retinitis pigmentosa or milder form of Bardet-Biedl syndrome. This variant is highly prevalent in patients of Arab-Muslim origin (Sharon and Banin. 2015. PubMed ID: 26261414; Hichri et al. 2005. PubMed ID: 15770229; Schmid et al. 2011. PubMed ID: 21520335; Hjortshøj et al. 2010. PubMed ID: 20120035). RT-PCR analysis indicated that this variant results in aberrant splicing. U1snRNA -mediated therapeutic approach to correct the splice defect in patient derived cell lines significantly increased correctly spliced BBS1 transcripts, which would suggest a high potential for gene therapy (Schmid et al. 2011. PubMed ID: 21520335). This variant is reported in 0.031% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. -

Bardet-Biedl syndrome Pathogenic:1
Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 160 of the BBS1 protein (p.Arg160Gln). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs376894444, gnomAD 0.03%). This missense change has been observed in individuals with Bardet-Biedl syndrome or nonsyndromic retinitis pigmentosa (PMID: 15770229, 21520335, 26261414). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 370228). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BBS1 protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
35
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.80
.;D;.;.
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Uncertain
0.44
T;T;T;T
MetaSVM
Uncertain
0.73
D
MutationAssessor
Uncertain
2.5
.;M;.;M
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-2.2
N;N;N;N
REVEL
Uncertain
0.60
Sift
Benign
0.13
T;T;T;D
Sift4G
Benign
0.10
T;T;D;T
Polyphen
1.0
.;D;.;.
Vest4
0.58
MVP
0.98
MPC
0.69
ClinPred
0.44
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.33
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.62
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.62
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376894444; hg19: chr11-66283057; API