rs55848325

Positions:

• chr11-66510683-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_024649.5(BBS1):​c.24T>C​(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: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (20 hom.)
• Consequence: BBS1 NM_024649.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 2.04

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]

ACMG classification

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, Benign=4, Uncertain_significance=1}. 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
BBS1	NM_024649.5	c.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
BBS1	ENST00000318312.12	c.24T>C	p.Asp8=	synonymous_variant	1/17	1	NM_024649.5	ENSP00000317469	P1

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 437 AN: 152228 Hom.: 2 Cov.: 32

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

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

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

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:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bardet-Biedl syndrome 1 Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 21, 2021	- -
Likely benign, no assertion criteria provided	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	Feb 25, 2015	- -
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 specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2018	Variant 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 submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	BBS1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

BBS1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2023

This 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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 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

Other links and lift over

dbSNP: rs55848325; hg19: chr11-66278154;