7-33505563-C-T

Position:

chr7-33505563-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_198428.3(BBS9):c.2216C>T(p.Ala739Val) variant causes a missense change. The variant allele was found at a frequency of 0.000566 in 1,614,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A739T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

BBS9
NM_198428.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.73

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073854923).

BP6

Variant 7-33505563-C-T is Benign according to our data. Variant chr7-33505563-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 210514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-33505563-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00273 (416/152344) while in subpopulation AFR AF= 0.0095 (395/41584). AF 95% confidence interval is 0.00873. There are 2 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS9	NM_198428.3 linkuse as main transcript	c.2216C>T	p.Ala739Val	missense_variant	20/23	ENST00000242067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS9	ENST00000242067.11 linkuse as main transcript	c.2216C>T	p.Ala739Val	missense_variant	20/23	1	NM_198428.3	P3	Q3SYG4-1

Frequencies

GnomAD3 genomes

AF:

0.00271

AC:

413

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00945

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000773

AC:

194

AN:

250868

Hom.:

AF XY:

0.000539

AC XY:

AN XY:

135546

show subpopulations

Gnomad AFR exome

AF:

0.0105

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000341

AC:

498

AN:

1461774

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

212

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0104

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000782

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.00273

AC:

416

AN:

152344

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

182

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00950

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000432

Hom.:

Bravo

AF:

0.00322

ESP6500AA

AF:

0.0138

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000955

AC:

116

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 24, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Bardet-Biedl syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

Bardet-Biedl syndrome 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Bardet-Biedl syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

T;.;.;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.097

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.90

D;D;D;D

MetaRNN

Benign

0.0074

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Benign

0.067

Sift

Benign

0.076

T;T;T;T

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.29

B;B;B;.

Vest4

0.25

MVP

0.33

MPC

0.063

ClinPred

0.012

GERP RS

4.9

Varity_R

0.13

gMVP

0.25

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

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