rs35676114

Positions:

• chr12-76346369-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_024685.4(BBS10):​c.1616C>T​(p.Pro539Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0728 in 1,613,816 control chromosomes in the GnomAD database, including 4,912 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.056 (328 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4584 hom.)
• Consequence: BBS10 NM_024685.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.305

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018639565).
• BP6: Variant 12-76346369-G-A is Benign according to our data. Variant chr12-76346369-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166721.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=8}. Variant chr12-76346369-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS10	NM_024685.4	c.1616C>T	p.Pro539Leu	missense_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.1616C>T	p.Pro539Leu	missense_variant	2/2		NM_024685.4	ENSP00000497413.1

Frequencies

GnomAD3 genomes AF: 0.0556 AC: 8454 AN: 152100 Hom.: 329 Cov.: 32

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0901

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0799

Gnomad OTH AF: 0.0613

GnomAD3 exomes AF: 0.0639 AC: 16057 AN: 251256 Hom.: 673 AF XY: 0.0682 AC XY: 9256 AN XY: 135798

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.0368

Gnomad ASJ exome AF: 0.0799

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0928

Gnomad FIN exome AF: 0.0631

Gnomad NFE exome AF: 0.0801

Gnomad OTH exome AF: 0.0777

GnomAD4 exome AF: 0.0746 AC: 109017 AN: 1461600 Hom.: 4584 Cov.: 33 AF XY: 0.0761 AC XY: 55338 AN XY: 727122

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.0384

Gnomad4 ASJ exome AF: 0.0794

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.0957

Gnomad4 FIN exome AF: 0.0596

Gnomad4 NFE exome AF: 0.0791

Gnomad4 OTH exome AF: 0.0763

GnomAD4 genome AF: 0.0555 AC: 8452 AN: 152216 Hom.: 328 Cov.: 32 AF XY: 0.0557 AC XY: 4145 AN XY: 74406

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.0501

Gnomad4 ASJ AF: 0.0801

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0914

Gnomad4 FIN AF: 0.0662

Gnomad4 NFE AF: 0.0799

Gnomad4 OTH AF: 0.0602

Alfa AF: 0.0746 Hom.: 727

Bravo AF: 0.0511

ESP6500AA AF: 0.0179 AC: 79

ESP6500EA AF: 0.0742 AC: 638

ExAC AF: 0.0647 AC: 7852

Asia WGS AF: 0.0320 AC: 112 AN: 3478

EpiCase AF: 0.0903

EpiControl AF: 0.0838

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Bardet-Biedl syndrome 10 Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Bardet-Biedl syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	research	SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 20498079) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.99
DANN	Benign	0.62
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.45	.;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.030	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.12
Sift	Benign	0.45	T;.
Sift4G	Benign	0.37	T;.
Polyphen		0.0010	B;B
Vest4		0.033
MPC		0.059
ClinPred		0.0028	T
GERP RS		0.79
Varity_R		0.025
gMVP		0.27

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: rs35676114; hg19: chr12-76740149;