rs309369

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152618.3(BBS12):c.378G>T(p.Glu126Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,782 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 70 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 81 hom. )

Consequence

BBS12
NM_152618.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0840

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001919955).

BP6

Variant 4-122742270-G-T is Benign according to our data. Variant chr4-122742270-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 262674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-122742270-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
BBS12	NM_152618.3 linkuse as main transcript	c.378G>T	p.Glu126Asp	missense_variant	2/2	ENST00000314218.8
BBS12	NM_001178007.2 linkuse as main transcript	c.378G>T	p.Glu126Asp	missense_variant	3/3
BBS12	XM_011531680.3 linkuse as main transcript	c.378G>T	p.Glu126Asp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
BBS12	ENST00000314218.8 linkuse as main transcript	c.378G>T	p.Glu126Asp	missense_variant	2/2	1	NM_152618.3	P1
BBS12	ENST00000542236.5 linkuse as main transcript	c.378G>T	p.Glu126Asp	missense_variant	3/3	2		P1
BBS12	ENST00000433287.1 linkuse as main transcript	c.378G>T	p.Glu126Asp	missense_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2673

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0616

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00430

AC:

1074

AN:

249912

Hom.:

AF XY:

0.00307

AC XY:

415

AN XY:

135202

show subpopulations

Gnomad AFR exome

AF:

0.0593

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00279

GnomAD4 exome

AF:

0.00173

AC:

2529

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1075

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.0633

Gnomad4 AMR exome

AF:

0.00275

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000549

Gnomad4 OTH exome

AF:

0.00346

GnomAD4 genome

AF:

0.0176

AC:

2675

AN:

152264

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

1256

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0614

Gnomad4 AMR

AF:

0.00555

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00357

Hom.:

Bravo

AF:

0.0202

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0617

AC:

272

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00530

AC:

643

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2016	- -

Bardet-Biedl syndrome 12

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

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

Bardet-Biedl syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.40

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.30

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.61

T;.;T

MetaRNN

Benign

0.0019

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.27

B;B;.

Vest4

0.19

MutPred

0.22

Loss of stability (P = 0.2295);Loss of stability (P = 0.2295);Loss of stability (P = 0.2295);

MVP

0.69

MPC

0.40

ClinPred

0.013

GERP RS

-1.5

Varity_R

0.21

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over