rs549625604

Positions:

• chr12-76347713-C-CA

Variant summary

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

The NM_024685.4(BBS10):​c.271_272insT​(p.Cys91LeufsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.000928 in 1,610,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. CH91F?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (0 hom.)
• Consequence: BBS10 NM_024685.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:35
• Conservation: PhyloP100: 4.30

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 49 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-76347713-C-CA is Pathogenic according to our data. Variant chr12-76347713-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 1328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS10	NM_024685.4	c.271_272insT	p.Cys91LeufsTer5	frameshift_variant	2/2	ENST00000650064.2	NP_078961.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS10	ENST00000650064.2	c.271_272insT	p.Cys91LeufsTer5	frameshift_variant	2/2		NM_024685.4	ENSP00000497413	P1

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 151960 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000579 AC: 144 AN: 248710 Hom.: 0 AF XY: 0.000586 AC XY: 79 AN XY: 134712

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000393

Gnomad FIN exome AF: 0.0000497

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000963 AC: 1404 AN: 1458528 Hom.: 0 Cov.: 33 AF XY: 0.000920 AC XY: 668 AN XY: 725798

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.000118

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.000796

GnomAD4 genome AF: 0.000592 AC: 90 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74330

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000926 Hom.: 0

Bravo AF: 0.000665

EpiCase AF: 0.000872

EpiControl AF: 0.000711

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:35

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 10 Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 15, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	Sanger sequencing showed a homozygous sequence variant in BBS10 gene resulting in frameshift. It is predicted as pathogenic by MutationTaster. This variant is classified as pathogenic which shows strong evidence of pathogenicity according to ACMG guidelines (Richards et al., 2015). Parents were heterozygous for the same variation. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 30, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM4,PP3,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_024685.3(BBS10):c.271dupT(C91Lfs*5) is classified as pathogenic in the context of Bardet-Biedl syndrome, BBS10-related. Sources cited for classification include the following: PMID 16582908, 20120035, 21209035, 20805367 and 24746959. Classification of NM_024685.3(BBS10):c.271dupT(C91Lfs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 02, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift duplication p.C91Lfs*5 in BBS10 (NM_024685.4) variant is known to be a common cause of Bardet-Biedl syndrome and is well-documented as a common founder mutation in several ethnic groups (Stoetzel C et al; Putoux A et al; Suspitsin et al). The variant has been reported to ClinVar as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The BBS10 c.271dupT (p.Cys91LeufsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Cys91LeufsTer5 is well-documented as a common founder mutation in several ethnic groups (Suspitsin et al. 2016). Stoetzel et al. (2006) sequenced 311 families with Bardet-Biedl syndrome (BBS) and found the p.Cys91LeufsTer5 variant in 18 patients in a homozygous state, 13 in a compound heterozygous state, and five in a heterozygous state, accounting for 46% of variants detected. BBS is known to follow a complex inheritance pattern; several individuals were found in this study who also carried a third variant in one of the other genes known to be associated with BBS. The p.Cys91LeufsTer5 variant has also been identified in a homozygous state in affected individuals from two families, one of Indian descent and one of Northern European descent; in a compound heterozygous state in a 20 year old woman with BBS; and in three fetal cases (Putoux et al. 2010; Lindstrand et al. 2014; Sathya Priya et al. 2015). Control data are unavailable for this variant which is reported at a frequency of 0.00121 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Cys91LeufsTer5 variant is classified as pathogenic for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2022	Frameshift variant predicted to result in protein truncation, as the last 633 amino acids are replaced with 4 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 20177705, 21463199, 27245532, 29974258, 24746959, 24400638, 16582908, 20472660, 25988237, 20805367, 28143435, 30614526, 30718709, 30947698, 28041643, 30312873, 29096039, 30767287, 32349990, 32581362, 24077912) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 08, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2016	- -

Bardet-Biedl syndrome Pathogenic:6

Pathogenic, flagged submission	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	MAGI'S LAB - Medical Genetics Laboratory, MAGI GROUP	Oct 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 14, 2017	Variant summary: The BBS10 c.271dupT (p.Cys91Leufs) variant results in a premature termination codon, predicted to cause a truncated or absent BBS10 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 81/119742 control chromosomes at a frequency of 0.0006765, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS10 variant (0.0013363). The variant of interest has been reported in multiple affected homozygous and compound heterozygous individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	provider interpretation	Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	Sep 15, 2018	- -
Pathogenic, criteria provided, single submitter	research	SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	Jan 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Cys91Leufs*5) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 633 amino acid(s) of the BBS10 protein. This variant is present in population databases (rs549625604, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 16582908, 20805367, 27385962). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1328). For these reasons, this variant has been classified as Pathogenic. -

Bardet-Biedl syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jul 17, 2014	This patient is a carrier of a heterozygous pathogenic variant in the BBS10 gene associated with for Bardet-Biedl syndrome 10. The BBS10 variant (c.271dup; p.Cys91Leufs*5) identified in this patient is a frameshift variant, reported to be one of the most common pathogenic variants for Bardet Biedl syndrome (Stoetzel et al. 2006, PMID: 16582908). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2022

The c.271dupT (p.C91Lfs*5) alteration, located in coding exon 2 of the BBS10 gene, consists of a duplication of T at position 271, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration occurs at the 3' terminus of the BBS10 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts 88% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This mutation has been reported both in homozygous and compound heterozygous form in 58 families with Bardet-Biedl syndrome (Stoetzel, 2006; Chen, 2011; Imhoff, 2011; Deveault, 2011; Janssen, 2011). Haplotyping data suggested that this is an ancient founder mutation found in several ethnic groups (Stoetzel, 2006). Based on the available evidence, this alteration is classified as pathogenic. -

BBS10-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The BBS10 c.271dupT variant is predicted to result in a frameshift and premature protein termination (p.Cys91Leufs*5). This variant has been reported in the homozygous state or along with a second variant in this gene in individuals with Bardet-Biedl syndrome (Mary et al. 2019. PubMed ID: 30614526) and found to be the most common disease-causing variant in BBS10 (Stoetzel et al. 2006. PubMed ID: 16582908). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in BBS10 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Bardet-biedl syndrome 6/10, digenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2010

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 09, 2017

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs549625604; hg19: chr12-76741493;