rs775081992

Variant names:

• chr7-33152811-C-T
• rs775081992
• NM_198428.3:c.223C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001348038.3(BBS9):​c.-55C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000753 in 1,461,610 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: BBS9 NM_001348038.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.503
• PP5: Variant 7-33152811-C-T is Pathogenic according to our data. Variant chr7-33152811-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 266106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-33152811-C-T is described in Lovd as [Pathogenic]. Variant chr7-33152811-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS9	NM_198428.3	c.223C>T	p.Arg75*	stop_gained	Exon 3 of 23	ENST00000242067.11	NP_940820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS9	ENST00000242067.11	c.223C>T	p.Arg75*	stop_gained	Exon 3 of 23	1	NM_198428.3	ENSP00000242067.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251294 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461610 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 9 Pathogenic:3

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome Pathogenic:2

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 04, 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.Arg75*) 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 (rs775081992, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of Bardet-Biedl syndrome (PMID: 31488071). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 266106). For these reasons, this variant has been classified as Pathogenic. -

BBS9-related disorder Pathogenic:1

Dec 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BBS9 c.223C>T variant is predicted to result in premature protein termination (p.Arg75*). This variant has been reported in the compound heterozygous state in two unrelated patients with Bardet-Biedl syndrome (Shaheen et al. 2016. PubMed ID: 27894351, Table S3; Niazi et al. 2019. PubMed ID: 31488071). We have detected this variant at PreventionGenetics in the compound heterozygous and homozygous states in two patients with BBS. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-33192423-C-T). Nonsense variants in BBS9 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Retinal vascular dystrophy Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.47, 0.43, 0.47
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs775081992; hg19: chr7-33192423; COSMIC: COSV54175241; COSMIC: COSV54175241;