rs35676114

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BA1

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P539P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.056 ( 328 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4584 hom. )

Consequence

BBS10
NM_024685.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 0.305

Publications

15 publications found

Variant links:

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

BBS10 links:

ENSG00000306428 (HGNC:):

ENSG00000306428 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 0.43507 (below the threshold of 3.09). GenCC associations: The gene is linked to Bardet-Biedl syndrome 10, ciliopathy, Bardet-Biedl syndrome.

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 VariationId is 166721.

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 rank	MANE	Protein	UniProt
BBS10	NM_024685.4 link	c.1616C>T	p.Pro539Leu	missense_variant	Exon 2 of 2	ENST00000650064.2	NP_078961.3	Q8TAM1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS10	ENST00000650064.2 link	c.1616C>T	p.Pro539Leu	missense_variant	Exon 2 of 2	NM_024685.4	ENSP00000497413.1	Q8TAM1
ENSG00000306428	ENST00000818399.1 link	n.175-788G>A		intron_variant	Intron 2 of 2
ENSG00000306428	ENST00000818400.1 link	n.202-788G>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0556

AC:

8454

AN:

152100

Hom.:

329

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0639

AC:

16057

AN:

251256

AF XY:

0.0682

show subpopulations

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 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.:

AF XY:

0.0761

AC XY:

55338

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.0125

AC:

418

AN:

33474

American (AMR)

AF:

0.0384

AC:

1718

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0794

AC:

2074

AN:

26126

East Asian (EAS)

AF:

0.000529

AC:

AN:

39682

South Asian (SAS)

AF:

0.0957

AC:

8251

AN:

86248

European-Finnish (FIN)

AF:

0.0596

AC:

3182

AN:

53408

Middle Eastern (MID)

AF:

0.141

AC:

815

AN:

5768

European-Non Finnish (NFE)

AF:

0.0791

AC:

87929

AN:

1111796

Other (OTH)

AF:

0.0763

AC:

4609

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

5754

11508

17262

23016

28770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3186

6372

9558

12744

15930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0555

AC:

8452

AN:

152216

Hom.:

328

Cov.:

AF XY:

0.0557

AC XY:

4145

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0144

AC:

599

AN:

41538

American (AMR)

AF:

0.0501

AC:

766

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0801

AC:

278

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.0914

AC:

440

AN:

4812

European-Finnish (FIN)

AF:

0.0662

AC:

701

AN:

10588

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0799

AC:

5436

AN:

68006

Other (OTH)

AF:

0.0602

AC:

127

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

404

809

1213

1618

2022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0710

Hom.:

956

Bravo

AF:

0.0511

ESP6500AA

AF:

0.0179

AC:

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:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 02, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome 10

Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 01, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome

Uncertain:1Benign:1

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20498079) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.99

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.32

T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.45

.;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.030

N;N

PhyloP100

0.30

PrimateAI

Benign

0.21

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

GERP RS

0.79

Varity_R

0.025

gMVP

0.27

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over