rs138072724

Positions:

chr7-33344585-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198428.3(BBS9):c.1280C>T(p.Ala427Val) variant causes a missense change. The variant allele was found at a frequency of 0.00724 in 1,613,792 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A427A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0057 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0074 ( 61 hom. )

Consequence

BBS9
NM_198428.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 6.05

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:

BBS9 (HGNC:):

BBS9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074636936).

BP6

Variant 7-33344585-C-T is Benign according to our data. Variant chr7-33344585-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194138.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=4}. Variant chr7-33344585-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-33344585-C-T is described in Lovd as [Likely_benign]. Variant chr7-33344585-C-T is described in Lovd as [Benign]. Variant chr7-33344585-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00574 (874/152244) while in subpopulation NFE AF= 0.00909 (618/68004). AF 95% confidence interval is 0.00849. There are 6 homozygotes in gnomad4. There are 435 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS9	NM_198428.3 linkuse as main transcript	c.1280C>T	p.Ala427Val	missense_variant	12/23	ENST00000242067.11	NP_940820.1	Q3SYG4-1A0A090N8P4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS9	ENST00000242067.11 linkuse as main transcript	c.1280C>T	p.Ala427Val	missense_variant	12/23	1	NM_198428.3	ENSP00000242067.6		Q3SYG4-1

Frequencies

GnomAD3 genomes

AF:

0.00575

AC:

874

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0152

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00909

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00493

AC:

1241

AN:

251488

Hom.:

AF XY:

0.00497

AC XY:

675

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.00755

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00740

AC:

10817

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00736

AC XY:

5349

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.000651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000754

Gnomad4 FIN exome

AF:

0.0111

Gnomad4 NFE exome

AF:

0.00874

Gnomad4 OTH exome

AF:

0.00542

GnomAD4 genome

AF:

0.00574

AC:

874

AN:

152244

Hom.:

Cov.:

AF XY:

0.00584

AC XY:

435

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0152

Gnomad4 NFE

AF:

0.00909

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00739

Hom.:

Bravo

AF:

0.00398

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.00463

AC:

562

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00682

EpiControl

AF:

0.00557

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BBS9: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 2016	The A427V variant in the BBS9 gene has been published previously as a rare sequence variant with a frequency of0.9% (Lim et al., 2014); this variant was identified in the homozygous state in 1/9033 control individuals. TheNHLBI Exome Sequencing Project reports A427V was observed in 0.79% (68/8600) alleles from individuals ofEuropean American ancestry, and was present in the homozygous state in one individual. The A427V variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure as these residues sharesimilar properties. This substitution occurs at a position where amino acids with similar properties to Alanine aretolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant isdamaging to the protein structure/function. We interpret A427V as a variant of uncertain significance. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Bardet-Biedl syndrome 9

Benign:1

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

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

0.23

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D

MetaRNN

Benign

0.0075

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.3

M;M;M;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.0

N;N;N;N

REVEL

Benign

0.28

Sift

Benign

0.27

T;T;T;T

Sift4G

Benign

0.24

T;T;T;T

Polyphen

1.0

D;D;D;.

Vest4

0.50

MVP

0.76

MPC

0.079

ClinPred

0.032

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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