NM_024649.5:c.416G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024649.5(BBS1):c.416G>A(p.Trp139*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000186 in 1,612,152 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BBS1
NM_024649.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 5.78

Publications

1 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 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS1 links:

ENSG00000256349 (HGNC:):

ENSG00000256349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-66514662-G-A is Pathogenic according to our data. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514662-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 241521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS1	NM_024649.5 link	c.416G>A	p.Trp139*	stop_gained	Exon 4 of 17	ENST00000318312.12	NP_078925.3	Q8NFJ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS1	ENST00000318312.12 link	c.416G>A	p.Trp139*	stop_gained	Exon 4 of 17	1	NM_024649.5	ENSP00000317469.7		Q8NFJ9-1
ENSG00000256349	ENST00000419755.3 link	c.527G>A	p.Trp176*	stop_gained	Exon 4 of 17	2		ENSP00000398526.3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249352

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460026

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726462

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome

Pathogenic:1Other:1

Oct 05, 2023

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.Trp139*) 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 (no rsID available, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with BBS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 241521). For these reasons, this variant has been classified as Pathogenic. -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Bardet-Biedl syndrome 1

Pathogenic:1

May 31, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2 -

BBS1-related disorder

Pathogenic:1

Jun 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BBS1 c.416G>A variant is predicted to result in premature protein termination (p.Trp139*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. Nonsense variants in BBS1 are expected to be pathogenic (see, Muller et al. 2010. PubMed ID: 20177705). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

PhyloP100

5.8

Vest4

0.39

ClinPred

0.93

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over