rs606231137

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_198428.3(BBS9):c.1877_1880del(p.Lys626ArgfsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000887 in 1,613,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

BBS9
NM_198428.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 6.72

Variant links:

Genes affected

BBS9 (HGNC:30000): (Bardet-Biedl syndrome 9) This gene is downregulated by parathyroid hormone in osteoblastic cells, and therefore is thought to be involved in parathyroid hormone action in bones. The exact function of this gene has not yet been determined. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jan 2017]

BBS9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 7-33383751-AAAAC-A is Pathogenic according to our data. Variant chr7-33383751-AAAAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-33383751-AAAAC-A is described in Lovd as [Pathogenic]. Variant chr7-33383751-AAAAC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS9	NM_198428.3 linkuse as main transcript	c.1877_1880del	p.Lys626ArgfsTer22	frameshift_variant	18/23	ENST00000242067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS9	ENST00000242067.11 linkuse as main transcript	c.1877_1880del	p.Lys626ArgfsTer22	frameshift_variant	18/23	1	NM_198428.3	P3	Q3SYG4-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000480

AC:

AN:

250072

Hom.:

AF XY:

0.0000666

AC XY:

AN XY:

135108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000917

AC:

134

AN:

1460740

Hom.:

AF XY:

0.0000977

AC XY:

AN XY:

726592

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000120

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000642

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000595

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 9

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 18, 2022	- -

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 05, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Bardet-Biedl syndrome 1

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 06, 2016	- -

BBS9-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2023

The BBS9 c.1877_1880delAACA variant is predicted to result in a frameshift and premature protein termination (p.Lys626Argfs*22). This variant has been reported in the homozygous and compound heterozygous states in individuals with Bardet-Biedl syndrome (Nishimura et al. 2005. PubMed ID: 16380913; Meyer et al. 2022. PubMed ID: 35112343). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in BBS9 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -

Bardet-Biedl syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change creates a premature translational stop signal (p.Lys626Argfs*22) in the BBS9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS9 are known to be pathogenic (PMID: 16380913, 20177705). This variant is present in population databases (rs774006614, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 16380913). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2662). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over