rs34737974

Positions:

chr12-76346354-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.279

Variant links:

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]

BBS10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS10	NM_024685.4 linkuse as main transcript	c.1631A>G	p.Asn544Ser	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 linkuse as main transcript	c.1631A>G	p.Asn544Ser	missense_variant	2/2		NM_024685.4	ENSP00000497413	P1

Frequencies

GnomAD3 genomes

AF:

0.00659

AC:

1003

AN:

152172

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00837

AC XY:

1136

AN XY:

135774

show subpopulations

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.:

Cov.:

AF XY:

0.00828

AC XY:

6022

AN XY:

727166

show subpopulations

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.:

Cov.:

AF XY:

0.00643

AC XY:

479

AN XY:

74458

show subpopulations

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.:

Bravo

AF:

0.00683

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00895

AC:

ExAC

AF:

0.00741

AC:

900

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.00971

EpiControl

AF:

0.00942

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Bardet-Biedl syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.48

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

LIST_S2

Benign

0.40

.;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.23

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over