11-66510683-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_024649.5(BBS1):ā€‹c.24T>Cā€‹(p.Asp8=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 1,614,192 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0029 ( 2 hom., cov: 32)
Exomes š‘“: 0.0040 ( 20 hom. )

Consequence

BBS1
NM_024649.5 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 2.04
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.65).
BP6
Variant 11-66510683-T-C is Benign according to our data. Variant chr11-66510683-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193457.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=4}. Variant chr11-66510683-T-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=2.04 with no splicing effect.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BBS1NM_024649.5 linkuse as main transcriptc.24T>C p.Asp8= synonymous_variant 1/17 ENST00000318312.12 NP_078925.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BBS1ENST00000318312.12 linkuse as main transcriptc.24T>C p.Asp8= synonymous_variant 1/171 NM_024649.5 ENSP00000317469 P1Q8NFJ9-1

Frequencies

GnomAD3 genomes
AF:
0.00287
AC:
437
AN:
152228
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00118
Gnomad ASJ
AF:
0.0132
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00641
Gnomad FIN
AF:
0.000659
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00453
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00402
AC:
1009
AN:
250784
Hom.:
5
AF XY:
0.00425
AC XY:
577
AN XY:
135676
show subpopulations
Gnomad AFR exome
AF:
0.000557
Gnomad AMR exome
AF:
0.00124
Gnomad ASJ exome
AF:
0.0153
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00647
Gnomad FIN exome
AF:
0.00107
Gnomad NFE exome
AF:
0.00493
Gnomad OTH exome
AF:
0.00376
GnomAD4 exome
AF:
0.00400
AC:
5851
AN:
1461846
Hom.:
20
Cov.:
33
AF XY:
0.00417
AC XY:
3036
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.000597
Gnomad4 AMR exome
AF:
0.00125
Gnomad4 ASJ exome
AF:
0.0151
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00603
Gnomad4 FIN exome
AF:
0.00144
Gnomad4 NFE exome
AF:
0.00403
Gnomad4 OTH exome
AF:
0.00429
GnomAD4 genome
AF:
0.00287
AC:
437
AN:
152346
Hom.:
2
Cov.:
32
AF XY:
0.00246
AC XY:
183
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.000409
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.0132
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00642
Gnomad4 FIN
AF:
0.000659
Gnomad4 NFE
AF:
0.00453
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00518
Hom.:
0
Bravo
AF:
0.00281
Asia WGS
AF:
0.00289
AC:
11
AN:
3478
EpiCase
AF:
0.00551
EpiControl
AF:
0.00433

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:12
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1 Uncertain:1Benign:4
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingNew York Genome CenterMar 21, 2021- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical CenterApr 19, 2017- -
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtFeb 25, 2015- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 specified Benign:4
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 10, 2018Variant summary: BBS1 c.24T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0039 in 276810 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS1 causing Bardet-Biedl Syndrome phenotype (0.00094), strongly suggesting that the variant is benign. The variant, c.24T>C, has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Gerth_2008, Deveault_2011, Hichri_2005) but in some cases not all BBS genes were tested. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 25, 2017- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 03, 2015- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024BBS1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
BBS1-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesNov 21, 2023This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Bardet-Biedl syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.65
CADD
Benign
12
DANN
Benign
0.66

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs55848325; hg19: chr11-66278154; API