chr11-66531692-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_024649.5(BBS1):c.1645G>T(p.Glu549*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

BBS1
NM_024649.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 8.85

Publications

15 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]

BBS1 links:

ENSG00000256349 (HGNC:):

ENSG00000256349 links:

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]

ZDHHC24 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.

PP5

Variant 11-66531692-G-T is Pathogenic according to our data. Variant chr11-66531692-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024649.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS1	NM_024649.5	MANE Select	c.1645G>T	p.Glu549*	stop_gained	Exon 16 of 17	NP_078925.3
	ZDHHC24	NM_001348571.2		c.560-2204C>A		intron	N/A	NP_001335500.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BBS1	ENST00000318312.12	TSL:1 MANE Select	c.1645G>T	p.Glu549*	stop_gained	Exon 16 of 17	ENSP00000317469.7
ENSG00000256349	ENST00000419755.3	TSL:2	c.1756G>T	p.Glu586*	stop_gained	Exon 16 of 17	ENSP00000398526.3
BBS1	ENST00000393994.4	TSL:1	c.1258G>T	p.Glu420*	stop_gained	Exon 13 of 13	ENSP00000377563.2

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251488

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112000

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000131

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41546

American (AMR)

AF:

0.00105

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000231

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1

Pathogenic:5

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 04, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The heterozygous p.Glu549Ter variant in BBS1 was identified by our study, along with another pathogenic variant, in 1 individual with Bardet-Biedl syndrome 1. The variant has been reported in at least 11 Puerto Rican and French individuals with Bardet-Biedl syndrome 1 (PMID: 12118255, 21517826, 24746959, 29641573, 15770229, 16327777), segregated with disease in 2 affected relatives from 2 families (PMID: 15770229, 16327777) and has been identified in 0.009% (3/34584) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121917777). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 12144) as pathogenic by OMIM, Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America, and as likely pathogenic by Counsyl. This nonsense variant leads to a premature termination codon at position 549. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the BBS1 gene is an established disease mechanism in autosomal recessive Bardet-Biedl syndrome 1. The presence of this variant in at least 2 affected homozygotes, in combination with a reported pathogenic variant, and in at least 11 individuals with Bardet-Biedl syndrome 1 increases the likelihood that the p.Glu549Ter variant is pathogenic (VariationID: 12143; PMID: 12118255). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Bardet-Biedl Syndrome 1. ACMG/AMP Criteria applied: PM3_very-strong, PP1_moderate, PM2, PVS1_moderate (Richards 2015).

Jun 12, 2025

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Mar 23, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Bardet-Biedl syndrome

Pathogenic:3

Jun 25, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mar 05, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BBS1 c.1645G>T (p.Glu549X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 251488 control chromosomes. c.1645G>T has been reported in the literature in multiple individuals affected with Bardet-Biedl Syndrome (Mykytyn_2002, Hichri_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12118255, 15770229). ClinVar contains an entry for this variant (Variation ID: 12144). Based on the evidence outlined above, the variant was classified as pathogenic.

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Glu549*) in the BBS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS1 are known to be pathogenic (PMID: 12118255, 21520335, 27032803). This variant is present in population databases (rs121917777, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 12118255, 15770229, 16327777, 21517826, 21642631, 22410627, 24746959). ClinVar contains an entry for this variant (Variation ID: 12144). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Inborn genetic diseases

Pathogenic:1

Nov 12, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1645G>T (p.E549*) alteration, located in exon 16 (coding exon 16) of the BBS1 gene, consists of a G to T substitution at nucleotide position 1645. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 549. This alteration occurs at the 3' terminus of the BBS1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 45/593 amino acids (7.6%) of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in the homozygous state and compound heterozygous state with various second disease-causing alterations in multiple patients with Bardet-Biedl syndrome (Mykytyn, 2002; Chen, 2011; Lindstrand, 2014; Sanchez-Navarro, 2018; Guardiola, 2021). Based on the available evidence, this alteration is classified as pathogenic.

not provided

Pathogenic:1

Apr 09, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 27788217, 21642631, 12118255, 21517826, 12677556, 16327777, 22410627, 24746959, 15770229, 31589614, 34792930, 32037395, 31345219, 35835773, 35119454, 37588308, 34526762)

BBS1-related disorder

Pathogenic:1

Jan 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BBS1 c.1645G>T variant is predicted to result in premature protein termination (p.Glu549*). This variant has been reported many times along with a second known causative variant or in the homozygous state in individuals with Bardet-Biedl syndrome or suspected non-syndromic retinitis pigmentosa (see for examples Mykytyn et al. 2002. PubMed ID: 12118255; Wang et al. 2016. PubMed ID: 27788217). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in BBS1 are expected to be pathogenic, and this variant has been classified as pathogenic by the majority of submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/12144). Given the evidence, we interpret c.1645G>T (p.Glu549*) as pathogenic.

Retinitis pigmentosa

Pathogenic:1

Apr 01, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Glu549Ter variant in BBS1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PS1, PM2. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

PhyloP100

8.8

Vest4

0.43

GERP RS

5.8

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over