rs1555050404

chr11-66531684-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024649.5(BBS1):c.1642del(p.Leu548TrpfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y546Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS1 NM_024649.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.14

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]

ACMG classification

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 11-66531684-AC-A is Pathogenic according to our data. Variant chr11-66531684-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS1	NM_024649.5	c.1642del	p.Leu548TrpfsTer31	frameshift_variant	16/17	ENST00000318312.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS1	ENST00000318312.12	c.1642del	p.Leu548TrpfsTer31	frameshift_variant	16/17	1	NM_024649.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 24, 2017	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Bardet-Biedl syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

This sequence change creates a premature translational stop signal (p.Leu548Trpfs*31) in the BBS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the BBS1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome and/or inherited retinal dystrophy (PMID: 12837689, 28143435, 36460718). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as L548fsX579. ClinVar contains an entry for this variant (Variation ID: 554520). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1555050404; hg19: chr11-66299155;