rs35520756

chr11-66519725-G-Achr11-66519725-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024649.5(BBS1):c.700G>A(p.Glu234Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00546 in 1,613,416 control chromosomes in the GnomAD database, including 409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (216 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (193 hom.)
• Consequence: BBS1 NM_024649.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 5.86

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036582947).
• BP6: Variant 11-66519725-G-A is Benign according to our data. Variant chr11-66519725-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 12148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66519725-G-A is described in Lovd as [Benign]. Variant chr11-66519725-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS1	NM_024649.5	c.700G>A	p.Glu234Lys	missense_variant	8/17	ENST00000318312.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS1	ENST00000318312.12	c.700G>A	p.Glu234Lys	missense_variant	8/17	1	NM_024649.5	P1
	ENST00000658548.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4464 AN: 151898 Hom.: 216 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.00768 AC: 1927 AN: 251044 Hom.: 94 AF XY: 0.00543 AC XY: 737 AN XY: 135726

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.00474

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00297 AC: 4343 AN: 1461400 Hom.: 193 Cov.: 31 AF XY: 0.00248 AC XY: 1800 AN XY: 727026

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000185

Gnomad4 OTH exome AF: 0.00606

GnomAD4 genome AF: 0.0294 AC: 4474 AN: 152016 Hom.: 216 Cov.: 32 AF XY: 0.0283 AC XY: 2100 AN XY: 74286

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00855 Hom.: 48

Bravo AF: 0.0339

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0995 AC: 438

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00928 AC: 1127

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -
Benign, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The BBS1 c.700G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: BS1, BS2. Based on this evidence we have classified this variant as Benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Bardet-Biedl syndrome Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2003	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 12567324, 20498079, 27894351, 29191167, 20981092, 27884173) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 23, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.0037	T;T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N;N;D;N
REVEL	Uncertain	0.55
Sift	Benign	0.089	T;T;T;T
Sift4G	Uncertain	0.034	D;D;D;T
Polyphen		0.99	.;D;.;.
Vest4		0.34
MVP		0.95
MPC		0.29
ClinPred		0.056	T
GERP RS		5.6
Varity_R		0.16
gMVP		0.58

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

Other links and lift over

dbSNP: rs35520756; hg19: chr11-66287196; COSMIC: COSV59150566; COSMIC: COSV59150566;