Genetic Variant BBS9:p.Val416Leu (chr7-33340944-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001348041.4(BBS9):c.1246G>C(p.Val416Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V416M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BBS9
NM_001348041.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.25

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049447477).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348041.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BBS9	NM_198428.3	MANE Select	c.1246G>C	p.Val416Leu	missense	Exon 11 of 23	NP_940820.1
BBS9	NM_001348041.4		c.1246G>C	p.Val416Leu	missense	Exon 11 of 23	NP_001334970.1
BBS9	NM_001348036.1		c.1246G>C	p.Val416Leu	missense	Exon 11 of 23	NP_001334965.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BBS9	ENST00000242067.11	TSL:1 MANE Select	c.1246G>C	p.Val416Leu	missense	Exon 11 of 23	ENSP00000242067.6
BBS9	ENST00000433714.5	TSL:1	n.1246G>C		non_coding_transcript_exon	Exon 11 of 24	ENSP00000412159.1
BBS9	ENST00000942912.1		c.1372G>C	p.Val458Leu	missense	Exon 12 of 24	ENSP00000612971.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461398

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726978

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111666

Other (OTH)

AF:

0.00

AC:

AN:

60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.0020

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.062

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.71

M_CAP

Benign

0.022

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.34

PhyloP100

-2.2

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.95

REVEL

Benign

0.14

Sift

Benign

0.42

Sift4G

Benign

0.66

Polyphen

0.0030

Vest4

0.13

MutPred

0.36

Loss of sheet (P = 0.0817)

MVP

0.41

MPC

0.063

ClinPred

0.15

GERP RS

-9.0

Varity_R

0.12

gMVP

0.14

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over