Genetic Variant BBS9:p.Ile617Leu (chr7-33383725-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198428.3(BBS9):c.1849A>C(p.Ile617Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00227 in 1,612,222 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 37 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 40 hom. )

Consequence

BBS9
NM_198428.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.75

Publications

4 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
BBS9-related 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=0.0043776035).

BP6

Variant 7-33383725-A-C is Benign according to our data. Variant chr7-33383725-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0117 (1781/152318) while in subpopulation AFR AF = 0.0405 (1681/41556). AF 95% confidence interval is 0.0388. There are 37 homozygotes in GnomAd4. There are 838 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 37 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198428.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BBS9	NM_198428.3	MANE Select	c.1849A>C	p.Ile617Leu	missense	Exon 18 of 23	NP_940820.1	Q3SYG4-1
BBS9	NM_001348041.4		c.1849A>C	p.Ile617Leu	missense	Exon 18 of 23	NP_001334970.1	A0A5F9ZH14
BBS9	NM_001348036.1		c.1849A>C	p.Ile617Leu	missense	Exon 18 of 23	NP_001334965.1	Q3SYG4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BBS9	ENST00000242067.11	TSL:1 MANE Select	c.1849A>C	p.Ile617Leu	missense	Exon 18 of 23	ENSP00000242067.6	Q3SYG4-1
BBS9	ENST00000434373.3	TSL:1	c.547A>C	p.Ile183Leu	missense	Exon 7 of 11	ENSP00000388114.1	H7BZ69
BBS9	ENST00000433714.5	TSL:1	n.*610A>C		non_coding_transcript_exon	Exon 19 of 24	ENSP00000412159.1	F8WCG5

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1777

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0405

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00318

AC:

790

AN:

248454

AF XY:

0.00247

show subpopulations

Gnomad AFR exome

AF:

0.0424

Gnomad AMR exome

AF:

0.00262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000892

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00129

AC:

1880

AN:

1459904

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

835

AN XY:

726110

show subpopulations

African (AFR)

AF:

0.0449

AC:

1502

AN:

33462

American (AMR)

AF:

0.00238

AC:

106

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.000268

AC:

AN:

85918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00179

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

0.0000585

AC:

AN:

1111048

Other (OTH)

AF:

0.00289

AC:

174

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0117

AC:

1781

AN:

152318

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

838

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0405

AC:

1681

AN:

41556

American (AMR)

AF:

0.00477

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68030

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

165

248

330

413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00518

Hom.:

Bravo

AF:

0.0143

ESP6500AA

AF:

0.0425

AC:

187

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00404

AC:

490

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Bardet-Biedl syndrome (1)

Bardet-Biedl syndrome 9 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0044

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

5.8

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.1

REVEL

Benign

0.040

Sift

Benign

0.12

Sift4G

Benign

0.32

Polyphen

0.0040

Vest4

0.53

MVP

0.32

MPC

0.065

ClinPred

0.0055

GERP RS

6.1

Varity_R

0.21

gMVP

0.27

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over