rs137852837

Positions:

• chr12-76347054-A-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_024685.4(BBS10):​c.931T>G​(p.Ser311Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,014 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BBS10 NM_024685.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.06

Genes affected

BBS10 (HGNC:26291): (Bardet-Biedl syndrome 10) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by progressive retinal degeneration, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse and the similar phenotypes exhibited by mutations in BBS gene family members is likely due to their shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene is likely not a ciliary protein but rather has distant sequence homology to type II chaperonins. As a molecular chaperone, this protein may affect the folding or stability of other ciliary or basal body proteins. Inhibition of this protein's expression impairs ciliogenesis in preadipocytes. Mutations in this gene cause Bardet-Biedl syndrome type 10. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78
• PP5: Variant 12-76347054-A-C is Pathogenic according to our data. Variant chr12-76347054-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 1331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-76347054-A-C is described in Lovd as [Pathogenic]. Variant chr12-76347054-A-C is described in Lovd as [Pathogenic]. Variant chr12-76347054-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS10	NM_024685.4	c.931T>G	p.Ser311Ala	missense_variant	2/2	ENST00000650064.2	NP_078961.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS10	ENST00000650064.2	c.931T>G	p.Ser311Ala	missense_variant	2/2		NM_024685.4	ENSP00000497413.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461014 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726880

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 05, 2022	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 311 of the BBS10 protein (p.Ser311Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 16823392, 26518167). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1331). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects BBS10 function (PMID: 20080638). -
Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	May 30, 2018	This patient is homozygous for the c.931T>G (p.Ser311Ala) variant in the BBS10 gene. This variant has been previously described in a large extended family with multiple individuals with Bardet-Biedl syndrome (Laurier et al. 2006. Eur J Hum Genet 14:1195-1203; Stoetzel et al. 2006 Nat Genet 38:521-524). This variant is considered to be pathogenic according to the ACMG guidelines. Homozygous or compound heterozygous mutations in BBS10 are associated with Bardet-Biedl syndrome-10 (OMIM #615987). The mode of inheritance is autosomal recessive. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2019

- -

Bardet-Biedl syndrome 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2006

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.59	.;T
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.97	N;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.018	D;.
Polyphen		0.95	P;P
Vest4		0.81
MutPred		0.66		Gain of catalytic residue at Q315 (P = 0.0452);Gain of catalytic residue at Q315 (P = 0.0452);
MVP		0.94
MPC		0.30
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.15
gMVP		0.58

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: rs137852837; hg19: chr12-76740834;