rs34737974

chr12-76346354-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024685.4(BBS10):c.1631A>G(p.Asn544Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 1,614,022 control chromosomes in the GnomAD database, including 75 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (69 hom.)
• Consequence: BBS10 NM_024685.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.279

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002981037).
• BP6: Variant 12-76346354-T-C is Benign according to our data. Variant chr12-76346354-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 166720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-76346354-T-C is described in Lovd as [Likely_benign]. Variant chr12-76346354-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00658 (1002/152290) while in subpopulation SAS AF= 0.0155 (75/4824). AF 95% confidence interval is 0.0127. There are 6 homozygotes in gnomad4. There are 479 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS10	NM_024685.4	c.1631A>G	p.Asn544Ser	missense_variant	2/2	ENST00000650064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS10	ENST00000650064.2	c.1631A>G	p.Asn544Ser	missense_variant	2/2		NM_024685.4	P1

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1003 AN: 152172 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00750

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00759 AC: 1908 AN: 251222 Hom.: 13 AF XY: 0.00837 AC XY: 1136 AN XY: 135774

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00576

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.00328

Gnomad NFE exome AF: 0.00808

Gnomad OTH exome AF: 0.00751

GnomAD4 exome AF: 0.00806 AC: 11788 AN: 1461732 Hom.: 69 Cov.: 32 AF XY: 0.00828 AC XY: 6022 AN XY: 727166

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.00566

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.00303

Gnomad4 NFE exome AF: 0.00799

Gnomad4 OTH exome AF: 0.00949

GnomAD4 genome AF: 0.00658 AC: 1002 AN: 152290 Hom.: 6 Cov.: 32 AF XY: 0.00643 AC XY: 479 AN XY: 74458

Gnomad4 AFR AF: 0.00293

Gnomad4 AMR AF: 0.00772

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0155

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.00750

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00798 Hom.: 15

Bravo AF: 0.00683

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00741 AC: 900

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.00971

EpiControl AF: 0.00942

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 03, 2021	Variant summary: BBS10 c.1631A>G (p.Asn544Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function and Asn544 is not located in a known functional domain of the Bardet-Biedl syndrome 10 protein. A functional study is consistent with the finding that this variant is a functional polymorphism (Zaghloul_2010) as the mutant was unable to rescue the morphant phenotype in zebrafish. The variant allele was found at a frequency of 0.0076 in 251414 control chromosomes, predominantly at a frequency of 0.016 within the South Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS10 causing Bardet-Biedl Syndrome phenotype (0.0012), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Three ClinVar submitters (evaluation after 2014) cite the variant as benign (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 11, 2018	- -

Bardet-Biedl syndrome 10 Benign:2

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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Sep 15, 2016

- -

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
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	4.8
Dann	Benign	0.46
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.34	N;.
REVEL	Benign	0.075
Sift	Benign	0.13	T;.
Sift4G	Benign	0.23	T;.
Polyphen		0.0	B;B
Vest4		0.055
MVP		0.46
MPC		0.050
ClinPred		0.0038	T
GERP RS		0.016
Varity_R		0.039
gMVP		0.18

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: rs34737974; hg19: chr12-76740134; COSMIC: COSV99060141;