11-66529892-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_024649.5(BBS1):c.1413C>T(p.Leu471=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,607,944 control chromosomes in the GnomAD database, including 43,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L471L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 3319 hom., cov: 31)

Exomes 𝑓: 0.23 ( 40111 hom. )

Consequence

BBS1
NM_024649.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.745

Variant links:

Genes affected

BBS1 (HGNC:966): (Bardet-Biedl syndrome 1) Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome. The encoded protein may play a role in eye, limb, cardiac and reproductive system development. [provided by RefSeq, Jul 2008]

BBS1 links:

ZDHHC24 (HGNC:27387): (zinc finger DHHC-type containing 24) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Predicted to be involved in peptidyl-L-cysteine S-palmitoylation and protein targeting to membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ZDHHC24 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 11-66529892-C-T is Benign according to our data. Variant chr11-66529892-C-T is described in ClinVar as [Benign]. Clinvar id is 261747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66529892-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.745 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS1	NM_024649.5 linkuse as main transcript	c.1413C>T	p.Leu471=	synonymous_variant	14/17	ENST00000318312.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS1	ENST00000318312.12 linkuse as main transcript	c.1413C>T	p.Leu471=	synonymous_variant	14/17	1	NM_024649.5	P1	Q8NFJ9-1

Frequencies

GnomAD3 genomes

AF:

0.180

AC:

27417

AN:

151950

Hom.:

3314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0431

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.155

Gnomad ASJ

AF:

0.150

Gnomad EAS

AF:

0.131

Gnomad SAS

AF:

0.194

Gnomad FIN

AF:

0.387

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.158

GnomAD3 exomes

AF:

0.203

AC:

49593

AN:

244460

Hom.:

5791

AF XY:

0.210

AC XY:

27807

AN XY:

132680

show subpopulations

Gnomad AFR exome

AF:

0.0376

Gnomad AMR exome

AF:

0.134

Gnomad ASJ exome

AF:

0.168

Gnomad EAS exome

AF:

0.124

Gnomad SAS exome

AF:

0.201

Gnomad FIN exome

AF:

0.384

Gnomad NFE exome

AF:

0.237

Gnomad OTH exome

AF:

0.201

GnomAD4 exome

AF:

0.228

AC:

332334

AN:

1455876

Hom.:

40111

Cov.:

AF XY:

0.229

AC XY:

165949

AN XY:

724504

show subpopulations

Gnomad4 AFR exome

AF:

0.0347

Gnomad4 AMR exome

AF:

0.136

Gnomad4 ASJ exome

AF:

0.167

Gnomad4 EAS exome

AF:

0.132

Gnomad4 SAS exome

AF:

0.207

Gnomad4 FIN exome

AF:

0.372

Gnomad4 NFE exome

AF:

0.240

Gnomad4 OTH exome

AF:

0.207

GnomAD4 genome

AF:

0.180

AC:

27429

AN:

152068

Hom.:

3319

Cov.:

AF XY:

0.186

AC XY:

13815

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0429

Gnomad4 AMR

AF:

0.156

Gnomad4 ASJ

AF:

0.150

Gnomad4 EAS

AF:

0.131

Gnomad4 SAS

AF:

0.194

Gnomad4 FIN

AF:

0.387

Gnomad4 NFE

AF:

0.242

Gnomad4 OTH

AF:

0.155

Alfa

AF:

0.221

Hom.:

7018

Bravo

AF:

0.155

Asia WGS

AF:

0.173

AC:

602

AN:

3478

EpiCase

AF:

0.221

EpiControl

AF:

0.229

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2016	Variant summary: The BBS1 c.1413C>T (p.Leu471Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a polymorphism outcome for this variant along with 5/5 splice prediction tools predicting the variant not to have an impact on normal splicing. This variant was found in 24241/116022 control chromosomes (2812 homozygotes) at a frequency of 0.2089345, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic BBS1 variant (0.0009449), suggesting this variant is likely a benign polymorphism. A clinical diagnostic laboratory ant at least one publication classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2020	- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Bardet-Biedl syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

Cadd

Benign

0.83

Dann

Benign

0.92

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