15-72735137-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033028.5(BBS4):c.1061T>C(p.Ile354Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 1,612,062 control chromosomes in the GnomAD database, including 303,685 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 23091 hom., cov: 32)

Exomes 𝑓: 0.61 ( 280594 hom. )

Consequence

BBS4
NM_033028.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.248

Publications

56 publications found

Variant links:

Genes affected

BBS4 (HGNC:969): (Bardet-Biedl syndrome 4) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse. The similar phenotypes exhibited by mutations in BBS gene family members are likely due to the protein's shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene has sequence similarity to O-linked N-acetylglucosamine (O-GlcNAc) transferases in plants and archaebacteria and in human forms a multi-protein "BBSome" complex with seven other BBS proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

BBS4 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS4 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=2.0739299E-6).

BP6

Variant 15-72735137-T-C is Benign according to our data. Variant chr15-72735137-T-C is described in ClinVar as Benign. ClinVar VariationId is 21734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS4	NM_033028.5 link	c.1061T>C	p.Ile354Thr	missense_variant	Exon 13 of 16	ENST00000268057.9	NP_149017.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS4	ENST00000268057.9 link	c.1061T>C	p.Ile354Thr	missense_variant	Exon 13 of 16	1	NM_033028.5	ENSP00000268057.4

Frequencies

GnomAD3 genomes

AF:

0.527

AC:

80060

AN:

151870

Hom.:

23108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.311

Gnomad AMI

AF:

0.697

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.673

Gnomad EAS

AF:

0.244

Gnomad SAS

AF:

0.586

Gnomad FIN

AF:

0.658

Gnomad MID

AF:

0.694

Gnomad NFE

AF:

0.644

Gnomad OTH

AF:

0.555

GnomAD2 exomes

AF:

0.573

AC:

144029

AN:

251154

AF XY:

0.587

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.497

Gnomad ASJ exome

AF:

0.674

Gnomad EAS exome

AF:

0.248

Gnomad FIN exome

AF:

0.662

Gnomad NFE exome

AF:

0.652

Gnomad OTH exome

AF:

0.609

GnomAD4 exome

AF:

0.613

AC:

895113

AN:

1460074

Hom.:

280594

Cov.:

AF XY:

0.616

AC XY:

447589

AN XY:

726432

show subpopulations

African (AFR)

AF:

0.307

AC:

10266

AN:

33462

American (AMR)

AF:

0.497

AC:

22232

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.675

AC:

17620

AN:

26114

East Asian (EAS)

AF:

0.229

AC:

9095

AN:

39684

South Asian (SAS)

AF:

0.601

AC:

51796

AN:

86226

European-Finnish (FIN)

AF:

0.662

AC:

35322

AN:

53378

Middle Eastern (MID)

AF:

0.632

AC:

3594

AN:

5690

European-Non Finnish (NFE)

AF:

0.639

AC:

709763

AN:

1110494

Other (OTH)

AF:

0.587

AC:

35425

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

17880

35760

53640

71520

89400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18542

37084

55626

74168

92710

<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:

0.527

AC:

80052

AN:

151988

Hom.:

23091

Cov.:

AF XY:

0.530

AC XY:

39337

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.311

AC:

12893

AN:

41468

American (AMR)

AF:

0.530

AC:

8095

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.673

AC:

2330

AN:

3462

East Asian (EAS)

AF:

0.245

AC:

1268

AN:

5170

South Asian (SAS)

AF:

0.585

AC:

2817

AN:

4814

European-Finnish (FIN)

AF:

0.658

AC:

6934

AN:

10540

Middle Eastern (MID)

AF:

0.682

AC:

199

AN:

292

European-Non Finnish (NFE)

AF:

0.644

AC:

43723

AN:

67944

Other (OTH)

AF:

0.549

AC:

1159

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1746

3492

5238

6984

8730

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

696

1392

2088

2784

3480

<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:

0.600

Hom.:

109140

Bravo

AF:

0.508

TwinsUK

AF:

0.642

AC:

2382

ALSPAC

AF:

0.648

AC:

2497

ESP6500AA

AF:

0.322

AC:

1416

ESP6500EA

AF:

0.640

AC:

5504

ExAC

AF:

0.573

AC:

69585

Asia WGS

AF:

0.395

AC:

1378

AN:

3478

EpiCase

AF:

0.647

EpiControl

AF:

0.653

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Dec 03, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 17, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Bardet-Biedl syndrome 4

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Bardet-Biedl syndrome

Benign:2

Oct 13, 2009

GeneReviews

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome 1

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

8.3

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.23

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.12

T;T

MetaRNN

Benign

0.0000021

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

.;N

PhyloP100

-0.25

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.19

.;N

REVEL

Benign

0.19

Sift

Benign

0.40

.;T

Sift4G

Benign

0.40

T;T

Polyphen

0.0

.;B

Vest4

0.066

MPC

0.012

ClinPred

0.0091

GERP RS

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.063

gMVP

0.15

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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