12-76347561-C-T

Position:

chr12-76347561-C-T

Variant summary

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

The NM_024685.4(BBS10):c.424G>A(p.Asp142Asn) variant causes a missense change. The variant allele was found at a frequency of 0.01 in 1,613,632 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 3 hom., cov: 32)

Exomes 𝑓: 0.010 ( 106 hom. )

Consequence

BBS10
NM_024685.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 5.20

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=0.0057961345).

BP6

Variant 12-76347561-C-T is Benign according to our data. Variant chr12-76347561-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 35752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-76347561-C-T is described in Lovd as [Benign]. Variant chr12-76347561-C-T is described in Lovd as [Likely_benign]. Variant chr12-76347561-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00712 (1083/152106) while in subpopulation NFE AF= 0.012 (819/67986). AF 95% confidence interval is 0.0114. There are 3 homozygotes in gnomad4. There are 513 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS10	NM_024685.4 linkuse as main transcript	c.424G>A	p.Asp142Asn	missense_variant	2/2	ENST00000650064.2	NP_078961.3	Q8TAM1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS10	ENST00000650064.2 linkuse as main transcript	c.424G>A	p.Asp142Asn	missense_variant	2/2		NM_024685.4	ENSP00000497413.1		Q8TAM1

Frequencies

GnomAD3 genomes

AF:

0.00713

AC:

1083

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00906

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00731

AC:

1825

AN:

249556

Hom.:

AF XY:

0.00731

AC XY:

988

AN XY:

135142

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.000599

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.00956

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.00707

GnomAD4 exome

AF:

0.0103

AC:

15123

AN:

1461526

Hom.:

106

Cov.:

AF XY:

0.00996

AC XY:

7243

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00235

Gnomad4 ASJ exome

AF:

0.000804

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00190

Gnomad4 FIN exome

AF:

0.0113

Gnomad4 NFE exome

AF:

0.0123

Gnomad4 OTH exome

AF:

0.00772

GnomAD4 genome

AF:

0.00712

AC:

1083

AN:

152106

Hom.:

Cov.:

AF XY:

0.00690

AC XY:

513

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00906

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00969

Hom.:

Bravo

AF:

0.00658

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00832

AC:

1010

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00916

EpiControl

AF:

0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 23, 2017	Variant summary: The c.424G>A (p.Asp142Asn) in BBS10 gene is a missense change that involves a mildly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. In In vivo experiments D142N was able to rescue the morphant phenotype similarly to the WT and was classified as "Benign" change (Zaghloul, 2010) (BS3). The variant was found in the large and broad cohorts of ExAC project at an allele frequency of 0.0083 (1005/120074 chrs tested), predominantly in individuals of European ancestry (0.0133; 878/65994, including 7/9 homozygotes). This observed frequencies exceed the maximal expected allele frequency of a disease causing BBS10 allele (0.0013) (BS1). The variant was identified in compound heterozygosity with BBS10 c.92C>T (p.P31L) in a BBS patient with a limited clinical information. It is not clear, whether c.424G>A was contributing to the clinical presentation of the patient or whether the real causal mutation may have been missed (Feuillan, 2011). In addition, the possibility of the variant being a modifier or a partner in a â€œtriallelic inheritanceâ€ cannot be completely ruled out. The variant was identified in Joubert Syndrome (JS) patient who carried two causative mutations in TME231 and was proposed to be a potential modifier. Lastly, the variant of interest has been reported as â€œLikely Benign/Benignâ€ by reputable databases/clinical laboratories (BP6). Taking together, by applying ACMG guidelines the variant was classified as Benign. -

Bardet-Biedl syndrome 10

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 20, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 14, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	BBS10: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Bardet-Biedl syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 11, 2014	- -

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

0.21

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

.;T

MetaRNN

Benign

0.0058

T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

N;.

REVEL

Uncertain

0.43

Sift

Benign

0.030

D;.

Sift4G

Benign

0.16

T;.

Polyphen

0.98

D;D

Vest4

0.40

MVP

0.94

MPC

0.36

ClinPred

0.034

GERP RS

5.3

Varity_R

0.14

gMVP

0.43

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