12-76347561-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_024685.4(BBS10):c.424G>A(p.Asp142Asn) variant causes a missense change. The variant allele was found at a frequency of 0.01 in 1,613,632 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D142D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 3 hom., cov: 32)

Exomes 𝑓: 0.010 ( 106 hom. )

Consequence

BBS10
NM_024685.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 5.20

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 -19 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=0.0057961345).

BP6

Variant 12-76347561-C-T is Benign according to our data. Variant chr12-76347561-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00712 (1083/152106) while in subpopulation NFE AF = 0.012 (819/67986). AF 95% confidence interval is 0.0114. There are 3 homozygotes in GnomAd4. There are 513 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS10	NM_024685.4 link	c.424G>A	p.Asp142Asn	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.424G>A	p.Asp142Asn	missense_variant	Exon 2 of 2	NM_024685.4	ENSP00000497413.1	Q8TAM1
ENSG00000306428	ENST00000818399.1 link	n.579C>T		non_coding_transcript_exon_variant	Exon 3 of 3
ENSG00000306428	ENST00000818400.1 link	n.606C>T		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00713

AC:

1083

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00906

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00731

AC:

1825

AN:

249556

AF XY:

0.00731

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.000599

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00956

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.00707

GnomAD4 exome

AF:

0.0103

AC:

15123

AN:

1461526

Hom.:

106

Cov.:

AF XY:

0.00996

AC XY:

7243

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33480

American (AMR)

AF:

0.00235

AC:

105

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000804

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00190

AC:

164

AN:

86256

European-Finnish (FIN)

AF:

0.0113

AC:

601

AN:

53112

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0123

AC:

13713

AN:

1111980

Other (OTH)

AF:

0.00772

AC:

466

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

862

1723

2585

3446

4308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

506

1012

1518

2024

2530

<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:

0.00712

AC:

1083

AN:

152106

Hom.:

Cov.:

AF XY:

0.00690

AC XY:

513

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41474

American (AMR)

AF:

0.00242

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000623

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00906

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0120

AC:

819

AN:

67986

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00991

Hom.:

Bravo

AF:

0.00658

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00832

AC:

1010

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00916

EpiControl

AF:

0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.424G>A (p.Asp142Asn) in BBS10 gene is a missense change that involves a mildly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. In In vivo experiments D142N was able to rescue the morphant phenotype similarly to the WT and was classified as "Benign" change (Zaghloul, 2010) (BS3). The variant was found in the large and broad cohorts of ExAC project at an allele frequency of 0.0083 (1005/120074 chrs tested), predominantly in individuals of European ancestry (0.0133; 878/65994, including 7/9 homozygotes). This observed frequencies exceed the maximal expected allele frequency of a disease causing BBS10 allele (0.0013) (BS1). The variant was identified in compound heterozygosity with BBS10 c.92C>T (p.P31L) in a BBS patient with a limited clinical information. It is not clear, whether c.424G>A was contributing to the clinical presentation of the patient or whether the real causal mutation may have been missed (Feuillan, 2011). In addition, the possibility of the variant being a modifier or a partner in a â€œtriallelic inheritanceâ€ cannot be completely ruled out. The variant was identified in Joubert Syndrome (JS) patient who carried two causative mutations in TME231 and was proposed to be a potential modifier. Lastly, the variant of interest has been reported as â€œLikely Benign/Benignâ€ by reputable databases/clinical laboratories (BP6). Taking together, by applying ACMG guidelines the variant was classified as Benign. -

Feb 21, 2018

Genetic Services Laboratory, University of Chicago

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

- -

Bardet-Biedl syndrome 10

Benign:3

Nov 14, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BBS10: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome 1

Benign:2

Apr 19, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 11, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

.;T

MetaRNN

Benign

0.0058

T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

5.2

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

N;.

REVEL

Uncertain

0.43

Sift

Benign

0.030

D;.

Sift4G

Benign

0.16

T;.

Polyphen

0.98

D;D

Vest4

0.40

MVP

0.94

MPC

0.36

ClinPred

0.034

GERP RS

5.3

Varity_R

0.14

gMVP

0.43

Mutation Taster

=82/18

polymorphism

(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