15-72735137-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 15/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a repeat TPR 9 (size 32) in uniprot entity BBS4_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_033028.5

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 id is 21734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72735137-T-C is described in Lovd as [Benign].

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	Q96RK4-1A0A0S2Z3A9

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		Q96RK4-1

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

GnomAD3 exomes

AF:

0.573

AC:

144029

AN:

251154

Hom.:

43579

AF XY:

0.587

AC XY:

79678

AN XY:

135756

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 SAS exome

AF:

0.601

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

Gnomad4 AFR exome

AF:

0.307

Gnomad4 AMR exome

AF:

0.497

Gnomad4 ASJ exome

AF:

0.675

Gnomad4 EAS exome

AF:

0.229

Gnomad4 SAS exome

AF:

0.601

Gnomad4 FIN exome

AF:

0.662

Gnomad4 NFE exome

AF:

0.639

Gnomad4 OTH exome

AF:

0.587

GnomAD4 genome

AF:

0.527

AC:

80052

AN:

151988

Hom.:

23091

Cov.:

AF XY:

0.530

AC XY:

39337

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.311

Gnomad4 AMR

AF:

0.530

Gnomad4 ASJ

AF:

0.673

Gnomad4 EAS

AF:

0.245

Gnomad4 SAS

AF:

0.585

Gnomad4 FIN

AF:

0.658

Gnomad4 NFE

AF:

0.644

Gnomad4 OTH

AF:

0.549

Alfa

AF:

0.618

Hom.:

76796

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

- -

Dec 17, 2013

Eurofins Ntd Llc (ga)

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

- -

not provided

Benign:2

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2009

GeneReviews

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

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

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

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

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

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