rs752762669

Positions:

chr4-122743421-CACAGATGCA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong

The NM_152618.3(BBS12):c.1531_1539delCAGATGCAA(p.Gln511_Gln513del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000502 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

BBS12
NM_152618.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.96

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_152618.3.

PP5

Variant 4-122743421-CACAGATGCA-C is Pathogenic according to our data. Variant chr4-122743421-CACAGATGCA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 434492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-122743421-CACAGATGCA-C is described in Lovd as [Likely_pathogenic]. Variant chr4-122743421-CACAGATGCA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS12	NM_152618.3 linkuse as main transcript	c.1531_1539delCAGATGCAA	p.Gln511_Gln513del	conservative_inframe_deletion	2/2	ENST00000314218.8	NP_689831.2	Q6ZW61
BBS12	NM_001178007.2 linkuse as main transcript	c.1531_1539delCAGATGCAA	p.Gln511_Gln513del	conservative_inframe_deletion	3/3		NP_001171478.1	Q6ZW61
BBS12	XM_011531680.3 linkuse as main transcript	c.1531_1539delCAGATGCAA	p.Gln511_Gln513del	conservative_inframe_deletion	2/2		XP_011529982.1	Q6ZW61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS12	ENST00000314218.8 linkuse as main transcript	c.1531_1539delCAGATGCAA	p.Gln511_Gln513del	conservative_inframe_deletion	2/2	1	NM_152618.3	ENSP00000319062.3		Q6ZW61
BBS12	ENST00000542236.5 linkuse as main transcript	c.1531_1539delCAGATGCAA	p.Gln511_Gln513del	conservative_inframe_deletion	3/3	2		ENSP00000438273.1		Q6ZW61

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251428

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135884

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:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461888

Hom.:

AF XY:

0.0000468

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.0000576

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000162

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 12

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 08, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 23, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 16, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 14, 2024	- -

Bardet-Biedl syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2023	Variant summary: BBS12 c.1531_1539delCAGATGCAA (p.Gln511_Gln513del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 4e-05 in 251428 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BBS12 causing Bardet-Biedl Syndrome (4e-05 vs 0.00076), allowing no conclusion about variant significance. c.1531_1539delCAGATGCAA has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Stoetzel_2006, Hjortshj_2010, Manara_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant affects protein function (Zaghloul_2010). The following publications have been ascertained in the context of this evaluation (PMID: 21463199, 31964843, 20120035, 30718709, 31196119, 20648243, 17160889, 20498079). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This variant, c.1531_1539del, results in the deletion of 3 amino acid(s) of the BBS12 protein (p.Gln511_Gln513del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752762669, gnomAD 0.007%). This variant has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 17160889, 20120035; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 434492). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects BBS12 function (PMID: 20498079). For these reasons, this variant has been classified as Pathogenic. -

BBS12-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

The BBS12 c.1531_1539del9 variant is predicted to result in an in-frame deletion (p.Gln511_Gln513del). This variant was reported in individuals with Bardet-Biedl syndrome (Stoetzel et al 2007. PubMed ID: 17160889; Hjortshøj et al. 2010. PubMed ID: 20120035). Functional studies using zebrafish suggest that this variant is deleterious (Supp. Table 4, Zaghloul et al. 2010. PubMed ID: 20498079). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 19, 2023

In-frame deletion of 3 amino acids in a non-repeat region; Published functional studies in zebrafish suggest a damaging effect (PMID: 20498079); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 30718709, 20120035, 17160889, 31196119, 20498079, 36938085, 31964843) -

Retinal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 16, 2018

- -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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