rs1553941580

chr4-122743841-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_152618.3(BBS12):c.1949C>G(p.Ser650Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,453,072 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S650S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BBS12 NM_152618.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.178

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-122743841-C-G is Pathogenic according to our data. Variant chr4-122743841-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS12	NM_152618.3	c.1949C>G	p.Ser650Ter	stop_gained	2/2	ENST00000314218.8
BBS12	NM_001178007.2	c.1949C>G	p.Ser650Ter	stop_gained	3/3
BBS12	XM_011531680.3	c.1949C>G	p.Ser650Ter	stop_gained	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS12	ENST00000314218.8	c.1949C>G	p.Ser650Ter	stop_gained	2/2	1	NM_152618.3	P1
BBS12	ENST00000542236.5	c.1949C>G	p.Ser650Ter	stop_gained	3/3	2		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1453072 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722176

Gnomad4 AFR exome AF: 0.00

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: 0.00000541

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 12 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Bardet-Biedl syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change creates a premature translational stop signal (p.Ser650*) in the BBS12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the BBS12 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BBS12-related conditions. ClinVar contains an entry for this variant (Variation ID: 553671). This variant disrupts a region of the BBS12 protein in which other variant(s) (p.Arg675*) have been determined to be pathogenic (PMID: 20827784, 21642631). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	35
Dann	Uncertain	0.98
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.096
FATHMM_MKL	Benign	0.087	N
MutationTaster	Benign	1.0	D;D
Vest4		0.057
GERP RS		2.6

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: rs1553941580; hg19: chr4-123664996;