rs13135778

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152618.3(BBS12):c.1399G>A(p.Asp467Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,613,942 control chromosomes in the GnomAD database, including 37,042 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D467D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.16 ( 2432 hom., cov: 33)

Exomes 𝑓: 0.21 ( 34610 hom. )

Consequence

BBS12
NM_152618.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.624

Publications

26 publications found

Variant links:

Genes affected

BBS12 (HGNC:26648): (Bardet-Biedl syndrome 12) The protein encoded by this gene is part of a complex that is involved in membrane trafficking. The encoded protein is a molecular chaperone that aids in protein folding upon ATP hydrolysis. This protein also plays a role in adipocyte differentiation. Defects in this gene are a cause of Bardet-Biedl syndrome type 12. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

BBS12 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Ambry Genetics, Myriad Women’s Health
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021182895).

BP6

Variant 4-122743291-G-A is Benign according to our data. Variant chr4-122743291-G-A is described in ClinVar as Benign. ClinVar VariationId is 166727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS12	NM_152618.3 link	c.1399G>A	p.Asp467Asn	missense_variant	Exon 2 of 2	ENST00000314218.8	NP_689831.2	Q6ZW61
BBS12	NM_001178007.2 link	c.1399G>A	p.Asp467Asn	missense_variant	Exon 3 of 3		NP_001171478.1	Q6ZW61
BBS12	XM_011531680.3 link	c.1399G>A	p.Asp467Asn	missense_variant	Exon 2 of 2		XP_011529982.1	Q6ZW61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS12	ENST00000314218.8 link	c.1399G>A	p.Asp467Asn	missense_variant	Exon 2 of 2	1	NM_152618.3	ENSP00000319062.3		Q6ZW61
BBS12	ENST00000542236.5 link	c.1399G>A	p.Asp467Asn	missense_variant	Exon 3 of 3	2		ENSP00000438273.1		Q6ZW61

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23917

AN:

152102

Hom.:

2432

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0626

Gnomad AMI

AF:

0.167

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.166

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.195

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.230

Gnomad OTH

AF:

0.153

GnomAD2 exomes

AF:

0.165

AC:

41447

AN:

251378

AF XY:

0.170

show subpopulations

Gnomad AFR exome

AF:

0.0609

Gnomad AMR exome

AF:

0.0826

Gnomad ASJ exome

AF:

0.166

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.200

Gnomad NFE exome

AF:

0.231

Gnomad OTH exome

AF:

0.181

GnomAD4 exome

AF:

0.209

AC:

305671

AN:

1461722

Hom.:

34610

Cov.:

AF XY:

0.208

AC XY:

151534

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.0603

AC:

2019

AN:

33478

American (AMR)

AF:

0.0868

AC:

3882

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.166

AC:

4336

AN:

26132

East Asian (EAS)

AF:

0.000453

AC:

AN:

39700

South Asian (SAS)

AF:

0.137

AC:

11822

AN:

86254

European-Finnish (FIN)

AF:

0.205

AC:

10945

AN:

53408

Middle Eastern (MID)

AF:

0.160

AC:

923

AN:

5768

European-Non Finnish (NFE)

AF:

0.234

AC:

260665

AN:

1111864

Other (OTH)

AF:

0.183

AC:

11061

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

13545

27090

40636

54181

67726

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8624

17248

25872

34496

43120

<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:

0.157

AC:

23917

AN:

152220

Hom.:

2432

Cov.:

AF XY:

0.153

AC XY:

11362

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0625

AC:

2596

AN:

41548

American (AMR)

AF:

0.123

AC:

1888

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.166

AC:

575

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5186

South Asian (SAS)

AF:

0.126

AC:

609

AN:

4826

European-Finnish (FIN)

AF:

0.195

AC:

2064

AN:

10584

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.230

AC:

15663

AN:

67990

Other (OTH)

AF:

0.150

AC:

317

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1021

2043

3064

4086

5107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.200

Hom.:

9542

Bravo

AF:

0.146

TwinsUK

AF:

0.231

AC:

856

ALSPAC

AF:

0.230

AC:

888

ESP6500AA

AF:

0.0690

AC:

304

ESP6500EA

AF:

0.226

AC:

1941

ExAC

AF:

0.170

AC:

20587

Asia WGS

AF:

0.0640

AC:

224

AN:

3478

EpiCase

AF:

0.222

EpiControl

AF:

0.220

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 21, 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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome 12

Benign:3

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome 1

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.061

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

2.8

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.087

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.13

T;.

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.1

N;N

PhyloP100

0.62

PrimateAI

Benign

0.31

PROVEAN

Benign

0.95

N;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;T

Sift4G

Benign

0.96

T;T

Polyphen

0.0

B;B

Vest4

0.018

MPC

0.081

ClinPred

0.00029

GERP RS

1.9

Varity_R

0.031

gMVP

0.20

Mutation Taster

=100/0

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