NM_198428.3:c.1363G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198428.3(BBS9):c.1363G>A(p.Ala455Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,610,110 control chromosomes in the GnomAD database, including 34,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2564 hom., cov: 32)

Exomes 𝑓: 0.21 ( 31525 hom. )

Consequence

BBS9
NM_198428.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.38

Publications

29 publications found

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 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.8375807E-4).

BP6

Variant 7-33349101-G-A is Benign according to our data. Variant chr7-33349101-G-A is described in ClinVar as Benign. ClinVar VariationId is 263117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS9	NM_198428.3 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 13 of 23	ENST00000242067.11	NP_940820.1	Q3SYG4-1A0A090N8P4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS9	ENST00000242067.11 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 13 of 23	1	NM_198428.3	ENSP00000242067.6		Q3SYG4-1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26979

AN:

152020

Hom.:

2562

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.185

Gnomad ASJ

AF:

0.179

Gnomad EAS

AF:

0.197

Gnomad SAS

AF:

0.206

Gnomad FIN

AF:

0.211

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.205

Gnomad OTH

AF:

0.182

GnomAD2 exomes

AF:

0.205

AC:

51549

AN:

251226

AF XY:

0.207

show subpopulations

Gnomad AFR exome

AF:

0.120

Gnomad AMR exome

AF:

0.226

Gnomad ASJ exome

AF:

0.186

Gnomad EAS exome

AF:

0.210

Gnomad FIN exome

AF:

0.215

Gnomad NFE exome

AF:

0.203

Gnomad OTH exome

AF:

0.192

GnomAD4 exome

AF:

0.205

AC:

298906

AN:

1457972

Hom.:

31525

Cov.:

AF XY:

0.206

AC XY:

149616

AN XY:

725512

show subpopulations

African (AFR)

AF:

0.112

AC:

3759

AN:

33422

American (AMR)

AF:

0.215

AC:

9631

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

4661

AN:

26092

East Asian (EAS)

AF:

0.171

AC:

6777

AN:

39580

South Asian (SAS)

AF:

0.230

AC:

19860

AN:

86166

European-Finnish (FIN)

AF:

0.213

AC:

11338

AN:

53248

Middle Eastern (MID)

AF:

0.165

AC:

949

AN:

5756

European-Non Finnish (NFE)

AF:

0.207

AC:

229811

AN:

1108750

Other (OTH)

AF:

0.201

AC:

12120

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

11975

23950

35924

47899

59874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8002

16004

24006

32008

40010

<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:

0.177

AC:

26997

AN:

152138

Hom.:

2564

Cov.:

AF XY:

0.177

AC XY:

13187

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.117

AC:

4877

AN:

41512

American (AMR)

AF:

0.185

AC:

2825

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

621

AN:

3472

East Asian (EAS)

AF:

0.197

AC:

1020

AN:

5184

South Asian (SAS)

AF:

0.205

AC:

991

AN:

4826

European-Finnish (FIN)

AF:

0.211

AC:

2227

AN:

10550

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.205

AC:

13913

AN:

67998

Other (OTH)

AF:

0.185

AC:

391

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1149

2298

3446

4595

5744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<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:

0.181

Hom.:

2024

Bravo

AF:

0.173

TwinsUK

AF:

0.219

AC:

811

ALSPAC

AF:

0.214

AC:

823

ESP6500AA

AF:

0.126

AC:

556

ESP6500EA

AF:

0.201

AC:

1727

ExAC

AF:

0.204

AC:

24791

Asia WGS

AF:

0.203

AC:

708

AN:

3478

EpiCase

AF:

0.203

EpiControl

AF:

0.198

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome 1

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome 9

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.027

T;.;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.095

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.61

T;T;T;T

MetaRNN

Benign

0.00088

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

N;N;N;N

PhyloP100

1.4

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.44

N;N;N;N

REVEL

Benign

0.045

Sift

Benign

0.23

T;T;T;T

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.066

MPC

0.097

ClinPred

0.0075

GERP RS

3.2

Varity_R

0.091

gMVP

0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over