rs1555202697

Positions:

• chr12-76347446-C-T

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.539G>A​(p.Gly180Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,478 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BBS10 NM_024685.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 5.20

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, 0.838
• PP5: Variant 12-76347446-C-T is Pathogenic according to our data. Variant chr12-76347446-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-76347446-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS10	NM_024685.4	c.539G>A	p.Gly180Glu	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.539G>A	p.Gly180Glu	missense_variant	2/2		NM_024685.4	ENSP00000497413.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461478 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 10 Pathogenic:2 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Counsyl	Nov 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 23, 2017	A homozygous missense variant was identified, NM_024685.3(BBS10):c.539G>A, in exon 2 of the BBS10 gene (Chr12:76741226). This substitution is predicted to create a change of a glycine to a glutamic acid at amino acid position 180, NP_078961.3(BBS10):p.(Gly180Glu). The glycine at this position has high conservation and is located in a TCP-1/cpn60 chaperonin family domain. Grantham assessment is likely pathogenic for this variant due to both amino acid properties and conservation. In silico software predicts this variant to be disease causing. This variant has not been previously observed in our patient cohort and has not been observed in population databases. It has been previously reported in a patient with Bardet-Biedl syndrome (Janssen S. et al, 2011). Subsequent testing of parental samples indicated that they are carriers of this variant. Based on current information this variant has been classified as LIKELY PATHOGENIC. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 08, 2024	- -

Bardet-Biedl syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 180 of the BBS10 protein (p.Gly180Glu). For these reasons, this variant has been classified as Pathogenic. 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 BBS10 protein function. ClinVar contains an entry for this variant (Variation ID: 488381). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 21052717, 32448990; Invitae). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.60		Gain of catalytic residue at A176 (P = 0.0191);Gain of catalytic residue at A176 (P = 0.0191);
MVP		0.91
MPC		0.41
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.59
gMVP		0.76

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: rs1555202697; hg19: chr12-76741226;