rs34218557

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198428.3(BBS9):c.1562G>A(p.Arg521Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,611,742 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0086 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00098 ( 22 hom. )

Consequence

BBS9
NM_198428.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.53

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072534382).

BP6

Variant 7-33357864-G-A is Benign according to our data. Variant chr7-33357864-G-A is described in ClinVar as [Benign]. Clinvar id is 263120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-33357864-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00859 (1302/151598) while in subpopulation AFR AF= 0.03 (1243/41396). AF 95% confidence interval is 0.0286. There are 15 homozygotes in gnomad4. There are 599 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS9	NM_198428.3 linkuse as main transcript	c.1562G>A	p.Arg521Gln	missense_variant	16/23	ENST00000242067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS9	ENST00000242067.11 linkuse as main transcript	c.1562G>A	p.Arg521Gln	missense_variant	16/23	1	NM_198428.3	P3	Q3SYG4-1

Frequencies

GnomAD3 genomes

AF:

0.00859

AC:

1301

AN:

151480

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00218

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000886

Gnomad OTH

AF:

0.00913

GnomAD3 exomes

AF:

0.00230

AC:

576

AN:

250662

Hom.:

AF XY:

0.00165

AC XY:

223

AN XY:

135494

show subpopulations

Gnomad AFR exome

AF:

0.0310

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000978

AC:

1428

AN:

1460144

Hom.:

Cov.:

AF XY:

0.000826

AC XY:

600

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.0329

Gnomad4 AMR exome

AF:

0.00161

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.00181

GnomAD4 genome

AF:

0.00859

AC:

1302

AN:

151598

Hom.:

Cov.:

AF XY:

0.00808

AC XY:

599

AN XY:

74088

show subpopulations

Gnomad4 AFR

AF:

0.0300

Gnomad4 AMR

AF:

0.00217

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000886

Gnomad4 OTH

AF:

0.00904

Alfa

AF:

0.000735

Hom.:

Bravo

AF:

0.0103

ESP6500AA

AF:

0.0343

AC:

151

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00291

AC:

353

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 19, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Bardet-Biedl syndrome 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bardet-Biedl syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.19

T;.;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.93

D;D;D;D

MetaRNN

Benign

0.0073

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.0

M;.;.;.

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Benign

0.080

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.79

P;P;P;.

Vest4

0.52

MVP

0.50

MPC

0.18

ClinPred

0.034

GERP RS

5.9

Varity_R

0.41

gMVP

0.55

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

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