rs1856202628

Variant names:

• chr11-66521261-TGTTTGCAGATG-T
• rs1856202628
• ENST00000526986:c.*216_*226delCATCTGCAAAC

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.724-8_726delGTTTGCAGATG​(p.Met242_Ser243del) variant causes a splice acceptor, conservative inframe deletion, splice region, 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, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ENSG00000256349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• 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 rank	MANE	Protein	UniProt
BBS1	NM_024649.5	c.724-8_726delGTTTGCAGATG	p.Met242_Ser243del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 9 of 17	ENST00000318312.12	NP_078925.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS1	ENST00000318312.12	c.724-8_726delGTTTGCAGATG	p.Met242_Ser243del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 9 of 17	1	NM_024649.5	ENSP00000317469.7
ENSG00000256349	ENST00000419755.3	c.835-8_837delGTTTGCAGATG	p.Met279_Ser280del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 9 of 17	2		ENSP00000398526.3

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 1 Pathogenic:1

Jun 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BBS1-related disorder Pathogenic:1

Feb 09, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 15, 2019

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome Pathogenic:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Bardet-Biedl syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 865945). For these reasons, this variant has been classified as Pathogenic. -

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;