rs869025210

Variant names:

• chr12-76346960-A-AT
• rs869025210
• NM_024685.4:c.1024dupA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024685.4(BBS10):​c.1024dupA​(p.Ile342AsnfsTer20) 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. I342I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS10 NM_024685.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.403
• Publications: 0 publications found

Genes affected

BBS10 (HGNC:26291): (Bardet-Biedl syndrome 10) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by progressive retinal degeneration, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse and the similar phenotypes exhibited by mutations in BBS gene family members is likely due to their shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene is likely not a ciliary protein but rather has distant sequence homology to type II chaperonins. As a molecular chaperone, this protein may affect the folding or stability of other ciliary or basal body proteins. Inhibition of this protein's expression impairs ciliogenesis in preadipocytes. Mutations in this gene cause Bardet-Biedl syndrome type 10. [provided by RefSeq, Jan 2010]

BBS10 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000306428 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 122 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-76346960-A-AT is Pathogenic according to our data. Variant chr12-76346960-A-AT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217439.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
BBS10	NM_024685.4	c.1024dupA	p.Ile342AsnfsTer20	frameshift_variant	Exon 2 of 2	ENST00000650064.2	NP_078961.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS10	ENST00000650064.2	c.1024dupA	p.Ile342AsnfsTer20	frameshift_variant	Exon 2 of 2		NM_024685.4	ENSP00000497413.1
ENSG00000306428	ENST00000818399.1	n.175-196dupT		intron_variant	Intron 2 of 2
ENSG00000306428	ENST00000818400.1	n.202-196dupT		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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 Pathogenic:2

Mar 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BBS10 protein in which other variant(s) (p.Val707*) have been determined to be pathogenic (PMID: 20472660, 22773737, 25982971, 27486776; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 217439). This premature translational stop signal has been observed in individual(s) with autosomal recessive Bardet-Biedl syndrome (PMID: 26518167). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile342Asnfs*20) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 382 amino acid(s) of the BBS10 protein. -

Apr 06, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Bardet-Biedl syndrome 10 Pathogenic:1

Oct 05, 2015

Department Of Medical Genetics, Faculty Of Medicine, Ege University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BBS10: PVS1:Strong, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.40
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs869025210; hg19: chr12-76740740;