rs35487251

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP2PP3BP6_Very_StrongBS1BS2

The NM_152384.3(BBS5):c.620G>A(p.Arg207His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00785 in 1,576,430 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R207C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0061 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 86 hom. )

Consequence

BBS5
NM_152384.3 missense, splice_region

Scores

Splicing: ADA: 0.9811

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 9.18

Publications

17 publications found

Variant links:

Genes affected

BBS5 (HGNC:970): (Bardet-Biedl syndrome 5) This gene encodes a protein that has been directly linked to Bardet-Biedl syndrome. The primary features of this syndrome include retinal dystrophy, obesity, polydactyly, renal abnormalities and learning disabilities. Experimentation in non-human eukaryotes suggests that this gene is expressed in ciliated cells and that it is required for the formation of cilia. Alternate transcriptional splice variants have been observed but have not been fully characterized. [provided by RefSeq, Jul 2008]

BBS5 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS5 links:

ENSG00000251569 (HGNC:):

ENSG00000251569 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.85025 (below the threshold of 3.09). Trascript score misZ: 1.0056 (below the threshold of 3.09). GenCC associations: The gene is linked to Bardet-Biedl syndrome 5, Bardet-Biedl syndrome.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 2-169497628-G-A is Benign according to our data. Variant chr2-169497628-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00612 (931/152124) while in subpopulation NFE AF = 0.00859 (584/67974). AF 95% confidence interval is 0.00801. There are 1 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 86 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS5	NM_152384.3 link	c.620G>A	p.Arg207His	missense_variant, splice_region_variant	Exon 8 of 12	ENST00000295240.8	NP_689597.1	Q8N3I7-1A0A0S2Z626

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS5	ENST00000295240.8 link	c.620G>A	p.Arg207His	missense_variant, splice_region_variant	Exon 8 of 12	1	NM_152384.3	ENSP00000295240.3		Q8N3I7-1
ENSG00000251569	ENST00000513963.1 link	c.620G>A	p.Arg207His	missense_variant, splice_region_variant	Exon 8 of 16	2		ENSP00000424363.1		E9PBE3

Frequencies

GnomAD3 genomes

AF:

0.00612

AC:

931

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00289

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00859

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.00656

AC:

1643

AN:

250580

AF XY:

0.00681

show subpopulations

Gnomad AFR exome

AF:

0.00242

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.00348

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.00884

Gnomad OTH exome

AF:

0.00508

GnomAD4 exome

AF:

0.00803

AC:

11437

AN:

1424306

Hom.:

Cov.:

AF XY:

0.00798

AC XY:

5667

AN XY:

710514

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

32702

American (AMR)

AF:

0.00300

AC:

134

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.00298

AC:

AN:

25854

East Asian (EAS)

AF:

0.00429

AC:

169

AN:

39358

South Asian (SAS)

AF:

0.00626

AC:

533

AN:

85078

European-Finnish (FIN)

AF:

0.0104

AC:

556

AN:

53360

Middle Eastern (MID)

AF:

0.00387

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00886

AC:

9559

AN:

1078514

Other (OTH)

AF:

0.00573

AC:

339

AN:

59150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

471

942

1414

1885

2356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

350

700

1050

1400

1750

<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:

0.00612

AC:

931

AN:

152124

Hom.:

Cov.:

AF XY:

0.00617

AC XY:

459

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00222

AC:

AN:

41512

American (AMR)

AF:

0.00334

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00289

AC:

AN:

3466

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.00643

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0135

AC:

143

AN:

10570

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00859

AC:

584

AN:

67974

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00670

Hom.:

Bravo

AF:

0.00512

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00341

AC:

ESP6500EA

AF:

0.00828

AC:

ExAC

AF:

0.00640

AC:

777

Asia WGS

AF:

0.00289

AC:

AN:

3472

EpiCase

AF:

0.00765

EpiControl

AF:

0.00735

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Oct 25, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 05, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BBS5 c.620G>A (p.Arg207His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0066 in 250580 control chromosomes in the gnomAD database, including 11 homozygotes. The observed variant frequency is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS5 causing Bardet-Biedl Syndrome phenotype (0.00062), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BBS5: BP4, BS2 -

Bardet-Biedl syndrome

Benign:1

Jan 26, 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

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.4

L;.

PhyloP100

9.2

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.23

Sift

Benign

0.12

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.83

P;.

Vest4

0.56

MVP

0.86

MPC

0.61

ClinPred

0.012

GERP RS

5.7

Varity_R

0.16

gMVP

0.35

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.84

Splicevardb

2.0

SpliceAI score (max)

0.11

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