GeneBe

rs775769424

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024649.5(BBS1):​c.1514_1515delTG​(p.Leu505ProfsTer52) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000142 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

BBS1
NM_024649.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.35
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]
ZDHHC24 (HGNC:27387): (zinc finger DHHC-type containing 24) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Predicted to be involved in peptidyl-L-cysteine S-palmitoylation and protein targeting to membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-66530933-CTG-C is Pathogenic according to our data. Variant chr11-66530933-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 371133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66530933-CTG-C is described in Lovd as [Pathogenic]. Variant chr11-66530933-CTG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BBS1NM_024649.5 linkc.1514_1515delTG p.Leu505ProfsTer52 frameshift_variant Exon 15 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.1514_1515delTG p.Leu505ProfsTer52 frameshift_variant Exon 15 of 17 1 NM_024649.5 ENSP00000317469.7 Q8NFJ9-1
ENSG00000256349ENST00000419755.3 linkc.1625_1626delTG p.Leu542ProfsTer52 frameshift_variant Exon 15 of 17 2 ENSP00000398526.3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152242
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461888
Hom.:
0
AF XY:
0.0000124
AC XY:
9
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1 Pathogenic:6
Apr 08, 2021
Ocular Genomics Institute, Massachusetts Eye and Ear
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

The BBS1 c.1514_1515del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PVS1, PP1. Based on this evidence we have classified this variant as Pathogenic. -

Feb 01, 2019
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 12, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 20, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 05, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 08, 2016
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Bardet-Biedl syndrome Pathogenic:2
Jun 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu505Profs*52) in the BBS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the BBS1 protein. This variant is present in population databases (rs775769424, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 12524598). ClinVar contains an entry for this variant (Variation ID: 371133). This variant disrupts a region of the BBS1 protein in which other variant(s) (p.Leu548Trpfs*31) have been determined to be pathogenic (PMID: 12677556, 12837689). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 06, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: BBS1 c.1514_1515delTG (p.Leu505ProfsX52) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251494 control chromosomes. c.1514_1515delTG has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Examples: Carrigan_2016, Deveault_2011, Jiman_2020 and Mykytyn_2003 etc.). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

BBS1-related disorder Pathogenic:1
Jun 10, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The BBS1 c.1514_1515delTG variant is predicted to result in a frameshift and premature protein termination (p.Leu505Profs*52). This variant has been reported to be causative for Bardet-Biedl syndrome (Mykytyn et al. 2003. PubMed ID: 12524598; Grudzinska Pechhacker et al. 2021. PubMed ID: 34940782). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in BBS1 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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: rs775769424; hg19: chr11-66298404; API