chr4-122742368-C-T

Position:

chr4-122742368-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The ENST00000314218.8(BBS12):c.476C>T(p.Pro159Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

BBS12
ENST00000314218.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 1.15

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.758

PP5

Variant 4-122742368-C-T is Pathogenic according to our data. Variant chr4-122742368-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555505.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
BBS12	NM_152618.3 linkuse as main transcript	c.476C>T	p.Pro159Leu	missense_variant	2/2	ENST00000314218.8	NP_689831.2
BBS12	NM_001178007.2 linkuse as main transcript	c.476C>T	p.Pro159Leu	missense_variant	3/3		NP_001171478.1
BBS12	XM_011531680.3 linkuse as main transcript	c.476C>T	p.Pro159Leu	missense_variant	2/2		XP_011529982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
BBS12	ENST00000314218.8 linkuse as main transcript	c.476C>T	p.Pro159Leu	missense_variant	2/2	1	NM_152618.3	ENSP00000319062	P1
BBS12	ENST00000542236.5 linkuse as main transcript	c.476C>T	p.Pro159Leu	missense_variant	3/3	2		ENSP00000438273	P1
BBS12	ENST00000433287.1 linkuse as main transcript	c.476C>T	p.Pro159Leu	missense_variant	3/3	2		ENSP00000398912

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251352

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 12

Pathogenic:1Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 11, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 20, 2024	- -

Retinal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 14, 2019

- -

Bardet-Biedl syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 159 of the BBS12 protein (p.Pro159Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with BBS12-related conditions (PMID: 22410627, 25982971). ClinVar contains an entry for this variant (Variation ID: 555505). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS12 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BBS12 function (PMID: 20080638, 20498079). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

BBS12-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2023

The BBS12 c.476C>T variant is predicted to result in the amino acid substitution p.Pro159Leu. This variant was reported in at least two individuals with Bardet-Biedl syndrome (Stoetzel et al. 2007. PubMed ID: 17160889; Scheidecker et al. 2015. PubMed ID: 25982971; Daniels et al. 2012. PubMed ID: 22410627; Chen et al. 2011. PubMed ID: 21642631). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-123663523-C-T). Functional studies are conflicting, one study concludes this variant as benign (Zaghloul NA et al 2010. PubMed ID: 20498079 Table S5), another study shows reduced protein interaction with BBS6, while interaction with BBS7 in unaffected (Seo et al. 2010. PubMed ID: 20080638). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.80

T;.;T

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.9

L;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.0

N;N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.019

D;D;D

Sift4G

Benign

0.063

T;T;D

Polyphen

0.013

B;B;.

Vest4

0.63

MutPred

0.90

Gain of catalytic residue at P159 (P = 0.0722);Gain of catalytic residue at P159 (P = 0.0722);Gain of catalytic residue at P159 (P = 0.0722);

MVP

0.78

MPC

0.47

ClinPred

0.35

GERP RS

3.4

Varity_R

0.063

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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