chr4-122742008-T-C

Position:

chr4-122742008-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_152618.3(BBS12):c.116T>C(p.Ile39Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00729 in 1,613,476 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0057 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0075 ( 53 hom. )

Consequence

BBS12
NM_152618.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 7.05

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009558558).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00568 (865/152324) while in subpopulation AMR AF= 0.0114 (175/15294). AF 95% confidence interval is 0.0101. There are 2 homozygotes in gnomad4. There are 387 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
BBS12	NM_152618.3 linkuse as main transcript	c.116T>C	p.Ile39Thr	missense_variant	2/2	ENST00000314218.8	NP_689831.2
BBS12	NM_001178007.2 linkuse as main transcript	c.116T>C	p.Ile39Thr	missense_variant	3/3		NP_001171478.1
BBS12	XM_011531680.3 linkuse as main transcript	c.116T>C	p.Ile39Thr	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.116T>C	p.Ile39Thr	missense_variant	2/2	1	NM_152618.3	ENSP00000319062	P1
BBS12	ENST00000542236.5 linkuse as main transcript	c.116T>C	p.Ile39Thr	missense_variant	3/3	2		ENSP00000438273	P1
BBS12	ENST00000433287.1 linkuse as main transcript	c.116T>C	p.Ile39Thr	missense_variant	3/3	2		ENSP00000398912

Frequencies

GnomAD3 genomes

AF:

0.00568

AC:

865

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00794

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00631

AC:

1584

AN:

251186

Hom.:

AF XY:

0.00689

AC XY:

935

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00550

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00534

Gnomad FIN exome

AF:

0.00250

Gnomad NFE exome

AF:

0.00862

Gnomad OTH exome

AF:

0.00948

GnomAD4 exome

AF:

0.00746

AC:

10893

AN:

1461152

Hom.:

Cov.:

AF XY:

0.00758

AC XY:

5511

AN XY:

726770

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00526

Gnomad4 ASJ exome

AF:

0.0147

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00471

Gnomad4 FIN exome

AF:

0.00227

Gnomad4 NFE exome

AF:

0.00829

Gnomad4 OTH exome

AF:

0.00706

GnomAD4 genome

AF:

0.00568

AC:

865

AN:

152324

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

387

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00794

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00828

Hom.:

Bravo

AF:

0.00587

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00608

AC:

738

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0114

EpiControl

AF:

0.0111

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 04, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2013	- -
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	Feb 22, 2022	Variant summary: BBS12 c.116T>C (p.Ile39Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0063 in 251186 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS12 causing Bardet-Biedl Syndrome phenotype (0.00076), strongly suggesting that the variant is benign. c.116T>C has been reported in the literature in individuals affected with Bardet-Biedl Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. At-least one co-occurrence with other pathogenic variant(s) have been reported (BBS12 c.814C>T, p.Arg272*), providing supporting evidence for a benign role (example, Manara_2019). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Zaghoul_2010). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. -

Bardet-Biedl syndrome 12

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 13, 2019	- -

Bardet-Biedl syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 22, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 19, 2017	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	BBS12: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 09, 2017	- -

Bardet-Biedl syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;D;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

T;.;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.0096

T;T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Uncertain

2.7

M;M;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.78

MVP

0.92

MPC

0.43

ClinPred

0.0081

GERP RS

5.0

Varity_R

0.83

gMVP

0.59

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