rs309370

chr4-122743049-G-Achr4-122743049-G-Cchr4-122743049-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_152618.3(BBS12):c.1157G>A(p.Arg386Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,613,888 control chromosomes in the GnomAD database, including 116,672 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.42 (14660 hom., cov: 33)
  • Exomes 𝑓: 0.36 (102012 hom.)
• Consequence: BBS12 NM_152618.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0820

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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-122743048-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=7.769768E-6).
• BP6: Variant 4-122743049-G-A is Benign according to our data. Variant chr4-122743049-G-A is described in ClinVar as [Benign]. Clinvar id is 166725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-122743049-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS12	NM_152618.3	c.1157G>A	p.Arg386Gln	missense_variant	2/2	ENST00000314218.8
BBS12	NM_001178007.2	c.1157G>A	p.Arg386Gln	missense_variant	3/3
BBS12	XM_011531680.3	c.1157G>A	p.Arg386Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS12	ENST00000314218.8	c.1157G>A	p.Arg386Gln	missense_variant	2/2	1	NM_152618.3	P1
BBS12	ENST00000542236.5	c.1157G>A	p.Arg386Gln	missense_variant	3/3	2		P1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64410 AN: 152020 Hom.: 14629 Cov.: 33

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.420

GnomAD3 exomes AF: 0.412 AC: 103503 AN: 251214 Hom.: 22936 AF XY: 0.408 AC XY: 55366 AN XY: 135810

Gnomad AFR exome AF: 0.563

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.663

Gnomad SAS exome AF: 0.473

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.340

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.365 AC: 533043 AN: 1461750 Hom.: 102012 Cov.: 60 AF XY: 0.367 AC XY: 267119 AN XY: 727168

Gnomad4 AFR exome AF: 0.561

Gnomad4 AMR exome AF: 0.487

Gnomad4 ASJ exome AF: 0.363

Gnomad4 EAS exome AF: 0.672

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.292

Gnomad4 NFE exome AF: 0.337

Gnomad4 OTH exome AF: 0.393

GnomAD4 genome AF: 0.424 AC: 64501 AN: 152138 Hom.: 14660 Cov.: 33 AF XY: 0.425 AC XY: 31587 AN XY: 74374

Gnomad4 AFR AF: 0.561

Gnomad4 AMR AF: 0.461

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.647

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.276

Gnomad4 NFE AF: 0.339

Gnomad4 OTH AF: 0.421

Alfa AF: 0.368 Hom.: 23089

Bravo AF: 0.446

TwinsUK AF: 0.333 AC: 1234

ALSPAC AF: 0.329 AC: 1269

ESP6500AA AF: 0.563 AC: 2479

ESP6500EA AF: 0.338 AC: 2903

ExAC AF: 0.414 AC: 50226

Asia WGS AF: 0.594 AC: 2063 AN: 3478

EpiCase AF: 0.341

EpiControl AF: 0.339

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Bardet-Biedl syndrome 12 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

Bardet-Biedl syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	7.1
Dann	Benign	0.76
DEOGEN2	Benign	0.078	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.23	T;.
MetaRNN	Benign	0.0000078	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.065
Sift	Benign	0.57	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0030	B;B
Vest4		0.019
MPC		0.097
ClinPred		0.0012	T
GERP RS		0.34
Varity_R		0.030
gMVP		0.28

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: rs309370; hg19: chr4-123664204; COSMIC: COSV58563061; COSMIC: COSV58563061;