chr11-66521262-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024649.5(BBS1):​c.724-8G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 1,611,188 control chromosomes in the GnomAD database, including 47,428 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4629 hom., cov: 32)
Exomes 𝑓: 0.24 ( 42799 hom. )

Consequence

BBS1
NM_024649.5 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00005736
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.690
Variant links:
Genes affected
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 11-66521262-G-C is Benign according to our data. Variant chr11-66521262-G-C is described in ClinVar as [Benign]. Clinvar id is 96131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66521262-G-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BBS1NM_024649.5 linkuse as main transcriptc.724-8G>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000318312.12
ZDHHC24NM_001348571.2 linkuse as main transcriptc.*226C>G 3_prime_UTR_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BBS1ENST00000318312.12 linkuse as main transcriptc.724-8G>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_024649.5 P1Q8NFJ9-1

Frequencies

GnomAD3 genomes
AF:
0.240
AC:
36436
AN:
152010
Hom.:
4621
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.230
Gnomad AMI
AF:
0.255
Gnomad AMR
AF:
0.181
Gnomad ASJ
AF:
0.151
Gnomad EAS
AF:
0.269
Gnomad SAS
AF:
0.202
Gnomad FIN
AF:
0.388
Gnomad MID
AF:
0.127
Gnomad NFE
AF:
0.242
Gnomad OTH
AF:
0.204
GnomAD3 exomes
AF:
0.232
AC:
58276
AN:
251346
Hom.:
7304
AF XY:
0.233
AC XY:
31687
AN XY:
135850
show subpopulations
Gnomad AFR exome
AF:
0.228
Gnomad AMR exome
AF:
0.147
Gnomad ASJ exome
AF:
0.169
Gnomad EAS exome
AF:
0.268
Gnomad SAS exome
AF:
0.208
Gnomad FIN exome
AF:
0.381
Gnomad NFE exome
AF:
0.237
Gnomad OTH exome
AF:
0.212
GnomAD4 exome
AF:
0.238
AC:
347625
AN:
1459060
Hom.:
42799
Cov.:
30
AF XY:
0.238
AC XY:
172899
AN XY:
726058
show subpopulations
Gnomad4 AFR exome
AF:
0.226
Gnomad4 AMR exome
AF:
0.149
Gnomad4 ASJ exome
AF:
0.168
Gnomad4 EAS exome
AF:
0.261
Gnomad4 SAS exome
AF:
0.215
Gnomad4 FIN exome
AF:
0.373
Gnomad4 NFE exome
AF:
0.240
Gnomad4 OTH exome
AF:
0.227
GnomAD4 genome
AF:
0.240
AC:
36469
AN:
152128
Hom.:
4629
Cov.:
32
AF XY:
0.244
AC XY:
18147
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.230
Gnomad4 AMR
AF:
0.181
Gnomad4 ASJ
AF:
0.151
Gnomad4 EAS
AF:
0.268
Gnomad4 SAS
AF:
0.202
Gnomad4 FIN
AF:
0.388
Gnomad4 NFE
AF:
0.242
Gnomad4 OTH
AF:
0.200
Alfa
AF:
0.194
Hom.:
1044
Bravo
AF:
0.223
Asia WGS
AF:
0.245
AC:
850
AN:
3478
EpiCase
AF:
0.222
EpiControl
AF:
0.229

ClinVar

Significance: Benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1 Benign:7
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterSep 21, 2015- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 10, 2021- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJun 02, 2017- -
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 09, 2014- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
not specified Benign:3
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 09, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 10, 2018- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Bardet-Biedl syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.86
CADD
Benign
6.3
DANN
Benign
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000057
dbscSNV1_RF
Benign
0.0020
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.

Other links and lift over

dbSNP: rs10896125; hg19: chr11-66288733; COSMIC: COSV59147680; COSMIC: COSV59147680; API