chr11-66529892-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_024649.5(BBS1):​c.1413C>T​(p.Leu471Leu) 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

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.745

Publications

38 publications found
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]
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.
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 rank MANE Protein UniProt
BBS1NM_024649.5 linkc.1413C>T p.Leu471Leu synonymous_variant Exon 14 of 17 ENST00000318312.12 NP_078925.3 Q8NFJ9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BBS1ENST00000318312.12 linkc.1413C>T p.Leu471Leu synonymous_variant Exon 14 of 17 1 NM_024649.5 ENSP00000317469.7 Q8NFJ9-1
ENSG00000256349ENST00000419755.3 linkc.1524C>T p.Leu508Leu synonymous_variant Exon 14 of 17 2 ENSP00000398526.3

Frequencies

GnomAD3 genomes
AF:
0.180
AC:
27417
AN:
151950
Hom.:
3314
Cov.:
31
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
GnomAD2 exomes
AF:
0.203
AC:
49593
AN:
244460
AF XY:
0.210
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 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.:
40
AF XY:
0.229
AC XY:
165949
AN XY:
724504
show subpopulations
African (AFR)
AF:
0.0347
AC:
1162
AN:
33476
American (AMR)
AF:
0.136
AC:
6080
AN:
44652
Ashkenazi Jewish (ASJ)
AF:
0.167
AC:
4360
AN:
26122
East Asian (EAS)
AF:
0.132
AC:
5232
AN:
39678
South Asian (SAS)
AF:
0.207
AC:
17873
AN:
86234
European-Finnish (FIN)
AF:
0.372
AC:
17819
AN:
47842
Middle Eastern (MID)
AF:
0.130
AC:
748
AN:
5768
European-Non Finnish (NFE)
AF:
0.240
AC:
266560
AN:
1111772
Other (OTH)
AF:
0.207
AC:
12500
AN:
60332
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
16464
32928
49392
65856
82320
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
8896
17792
26688
35584
44480
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.180
AC:
27429
AN:
152068
Hom.:
3319
Cov.:
31
AF XY:
0.186
AC XY:
13815
AN XY:
74304
show subpopulations
African (AFR)
AF:
0.0429
AC:
1783
AN:
41518
American (AMR)
AF:
0.156
AC:
2386
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.150
AC:
520
AN:
3472
East Asian (EAS)
AF:
0.131
AC:
678
AN:
5162
South Asian (SAS)
AF:
0.194
AC:
934
AN:
4810
European-Finnish (FIN)
AF:
0.387
AC:
4086
AN:
10556
Middle Eastern (MID)
AF:
0.126
AC:
37
AN:
294
European-Non Finnish (NFE)
AF:
0.242
AC:
16443
AN:
67962
Other (OTH)
AF:
0.155
AC:
328
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
1078
2155
3233
4310
5388
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
296
592
888
1184
1480
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.210
Hom.:
9989
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:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1 Benign:4
Jun 02, 2017
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 10, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 16, 2020
Natera, Inc.
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not provided Benign:3
Sep 15, 2020
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 18, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Retinal dystrophy Benign:1
Oct 01, 2023
Dept Of Ophthalmology, Nagoya University
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:research

- -

Bardet-Biedl syndrome Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
CADD
Benign
0.83
DANN
Benign
0.92
PhyloP100
-0.74
Mutation Taster
=99/1
polymorphism (auto)

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

Other links and lift over

dbSNP: rs3816492; hg19: chr11-66297363; COSMIC: COSV59147234; COSMIC: COSV59147234; API