rs17006092

chr4-122743101-G-Achr4-122743101-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152618.3(BBS12):c.1209G>A(p.Val403=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,614,194 control chromosomes in the GnomAD database, including 551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V403V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.033 (170 hom., cov: 33)
  • Exomes 𝑓: 0.018 (381 hom.)
• Consequence: BBS12 NM_152618.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.831

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-122743101-G-A is Benign according to our data. Variant chr4-122743101-G-A is described in ClinVar as [Benign]. Clinvar id is 262670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-122743101-G-A is described in Lovd as [Benign]. Variant chr4-122743101-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.831 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS12	NM_152618.3	c.1209G>A	p.Val403=	synonymous_variant	2/2	ENST00000314218.8
BBS12	NM_001178007.2	c.1209G>A	p.Val403=	synonymous_variant	3/3
BBS12	XM_011531680.3	c.1209G>A	p.Val403=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS12	ENST00000314218.8	c.1209G>A	p.Val403=	synonymous_variant	2/2	1	NM_152618.3	P1
BBS12	ENST00000542236.5	c.1209G>A	p.Val403=	synonymous_variant	3/3	2		P1

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 5043 AN: 152214 Hom.: 167 Cov.: 33

Gnomad AFR AF: 0.0787

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0174 AC: 4380 AN: 251454 Hom.: 97 AF XY: 0.0159 AC XY: 2159 AN XY: 135906

Gnomad AFR exome AF: 0.0815

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00443

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0182 AC: 26630 AN: 1461862 Hom.: 381 Cov.: 68 AF XY: 0.0173 AC XY: 12608 AN XY: 727230

Gnomad4 AFR exome AF: 0.0771

Gnomad4 AMR exome AF: 0.0158

Gnomad4 ASJ exome AF: 0.0298

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00565

Gnomad4 NFE exome AF: 0.0186

Gnomad4 OTH exome AF: 0.0226

GnomAD4 genome AF: 0.0333 AC: 5067 AN: 152332 Hom.: 170 Cov.: 33 AF XY: 0.0322 AC XY: 2398 AN XY: 74506

Gnomad4 AFR AF: 0.0791

Gnomad4 AMR AF: 0.0243

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0209 Hom.: 48

Bravo AF: 0.0370

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Bardet-Biedl syndrome 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Bardet-Biedl syndrome 12 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

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
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.077
Dann	Benign	0.52

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: rs17006092; hg19: chr4-123664256;