rs776730549

Positions:

• chr4-122743466-G-A
• chr4-122743466-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_152618.3(BBS12):​c.1574G>A​(p.Arg525His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,892 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: BBS12 NM_152618.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 8.99

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 4-122743466-G-A is Pathogenic according to our data. Variant chr4-122743466-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220303.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS12	NM_152618.3	c.1574G>A	p.Arg525His	missense_variant	2/2	ENST00000314218.8	NP_689831.2
BBS12	NM_001178007.2	c.1574G>A	p.Arg525His	missense_variant	3/3		NP_001171478.1
BBS12	XM_011531680.3	c.1574G>A	p.Arg525His	missense_variant	2/2		XP_011529982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS12	ENST00000314218.8	c.1574G>A	p.Arg525His	missense_variant	2/2	1	NM_152618.3	ENSP00000319062.3
BBS12	ENST00000542236.5	c.1574G>A	p.Arg525His	missense_variant	3/3	2		ENSP00000438273.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251462 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461892 Hom.: 0 Cov.: 35 AF XY: 0.0000275 AC XY: 20 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bardet-Biedl syndrome 12 Pathogenic:2 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2017	- -
Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Bardet-Biedl syndrome 12, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium . -

Bardet-Biedl syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	provider interpretation	Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	Sep 15, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 525 of the BBS12 protein (p.Arg525His). This variant is present in population databases (rs776730549, gnomAD 0.003%). This missense change has been observed in individual(s) with BBS12-related disease (PMID: 20472660, 30614526). 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: 220303). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS12 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

BBS12-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2024

The BBS12 c.1574G>A variant is predicted to result in the amino acid substitution p.Arg525His. This variant along with a second variant in BBS12 has been reported in two patients with Bardet-Biedl / McKusick-Kaufman syndrome phenotype (Table S1, Billingsley et al. 2010. PubMed ID: 20472660; Table 1, Mary et al. 2019. PubMed ID: 30614526). We have also seen this variant in the compound heterozygous state with a frameshift variant in BBS12 in a patient tested at PreventionGenetics with Bardet-Biedl syndrome. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;.
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.96	D;D
Vest4		0.77
MutPred		0.83		Gain of glycosylation at T521 (P = 0.0595);Gain of glycosylation at T521 (P = 0.0595);
MVP		0.90
MPC		0.51
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.60
gMVP		0.74

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: rs776730549; hg19: chr4-123664621; COSMIC: COSV58561688; COSMIC: COSV58561688;