11-66521261-TGTTTGCAGATG-T

Position:

• chr11-66521261-TGTTTGCAGATG-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_024649.5(BBS1):​c.724-8_726del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS1 NM_024649.5 splice_acceptor, coding_sequence, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.62

Genes affected

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.4, offset of 20, new splice context is: cagcgtccccgtcttcctAGagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-66521261-TGTTTGCAGATG-T is Pathogenic according to our data. Variant chr11-66521261-TGTTTGCAGATG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 865945.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.724-8_726del		splice_acceptor_variant, coding_sequence_variant, intron_variant	9/17	ENST00000318312.12
ZDHHC24	NM_001348571.2	c.*216_*226del		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS1	ENST00000318312.12	c.724-8_726del		splice_acceptor_variant, coding_sequence_variant, intron_variant	9/17	1	NM_024649.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BBS1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2023

The BBS1 c.724-8_726del11 variant is predicted to result in a deletion affecting a canonical splice site. This variant deletes the canonical splice acceptor site; an alternative splice acceptor is created that is predicted to introduce a frameshift (p.?). This variant has been reported in the compound heterozygous state with a well-established pathogenic variant in an individual with Bardet-Biedl syndrome (Billingsley et al. 2010. PubMed ID: 20472660; Grudzinska Pechhacker et al. 2021. PubMed ID: 34940782). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Frameshift variants in BBS1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jun 15, 2019

- -

Bardet-Biedl syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 865945). This variant has been observed in individuals with clinical features of Bardet-Biedl syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 9 (c.724-8_726del) of the BBS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BBS1 are known to be pathogenic (PMID: 12118255, 21520335, 27032803). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1856202628; hg19: chr11-66288732;