rs309358

Positions:

• chr4-122732771-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152618.3(BBS12):​c.-124G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,466 control chromosomes in the GnomAD database, including 3,498 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3494 hom., cov: 33)
  • Exomes 𝑓: 0.23 (4 hom.)
• Consequence: BBS12 NM_152618.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.452

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-122732771-G-A is Benign according to our data. Variant chr4-122732771-G-A is described in ClinVar as [Benign]. Clinvar id is 347494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-122732771-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS12	NM_152618.3	c.-124G>A		5_prime_UTR_variant	1/2	ENST00000314218.8	NP_689831.2
BBS12	NM_001178007.2	c.-312G>A		5_prime_UTR_variant	1/3		NP_001171478.1
BBS12	XM_011531680.3	c.-10-9112G>A		intron_variant			XP_011529982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS12	ENST00000314218.8	c.-124G>A		5_prime_UTR_variant	1/2	1	NM_152618.3	ENSP00000319062	P1
BBS12	ENST00000542236.5	c.-312G>A		5_prime_UTR_variant	1/3	2		ENSP00000438273	P1
BBS12	ENST00000433287.1			upstream_gene_variant		2		ENSP00000398912

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31138 AN: 152134 Hom.: 3493 Cov.: 33

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.229 AC: 49 AN: 214 Hom.: 4 Cov.: 0 AF XY: 0.263 AC XY: 42 AN XY: 160

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.205 AC: 31158 AN: 152252 Hom.: 3494 Cov.: 33 AF XY: 0.199 AC XY: 14784 AN XY: 74426

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.184

Alfa AF: 0.226 Hom.: 809

Bravo AF: 0.201

Asia WGS AF: 0.0740 AC: 256 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Bardet-Biedl syndrome 12 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.9
DANN	Benign	0.75

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: rs309358; hg19: chr4-123653926;