rs138036823

Positions:

• chr4-122742008-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 7.05

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]

ACMG classification

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	UniProt
BBS12	NM_152618.3	c.116T>C	p.Ile39Thr	missense_variant	2/2	ENST00000314218.8
BBS12	NM_001178007.2	c.116T>C	p.Ile39Thr	missense_variant	3/3
BBS12	XM_011531680.3	c.116T>C	p.Ile39Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS12	ENST00000314218.8	c.116T>C	p.Ile39Thr	missense_variant	2/2	1	NM_152618.3	P1
BBS12	ENST00000542236.5	c.116T>C	p.Ile39Thr	missense_variant	3/3	2		P1
BBS12	ENST00000433287.1	c.116T>C	p.Ile39Thr	missense_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00568 AC: 865 AN: 152206 Hom.: 2 Cov.: 33

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.: 6 AF XY: 0.00689 AC XY: 935 AN XY: 135752

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.: 53 Cov.: 31 AF XY: 0.00758 AC XY: 5511 AN XY: 726770

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.: 2 Cov.: 33 AF XY: 0.00520 AC XY: 387 AN XY: 74490

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.: 9

Bravo AF: 0.00587

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00608 AC: 738

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0114

EpiControl AF: 0.0111

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2013	- -
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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Bardet-Biedl syndrome 12 Uncertain:2 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 13, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
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	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -

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

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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T;.;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs138036823; hg19: chr4-123663163;