chr15-72709760-A-G

Position:

chr15-72709760-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_033028.5(BBS4):c.137A>G(p.Lys46Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00891 in 1,613,402 control chromosomes in the GnomAD database, including 97 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0064 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0092 ( 94 hom. )

Consequence

BBS4
NM_033028.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 6.34

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008608013).

BP6

Variant 15-72709760-A-G is Benign according to our data. Variant chr15-72709760-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196570.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=6}. Variant chr15-72709760-A-G is described in Lovd as [Likely_benign]. Variant chr15-72709760-A-G is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS4	NM_033028.5 link	c.137A>G	p.Lys46Arg	missense_variant	3/16	ENST00000268057.9	NP_149017.2	Q96RK4-1A0A0S2Z3A9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS4	ENST00000268057.9 link	c.137A>G	p.Lys46Arg	missense_variant	3/16	1	NM_033028.5	ENSP00000268057.4		Q96RK4-1

Frequencies

GnomAD3 genomes

AF:

0.00643

AC:

979

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00812

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00995

Gnomad OTH

AF:

0.0119

GnomAD3 exomes

AF:

0.00687

AC:

1726

AN:

251304

Hom.:

AF XY:

0.00692

AC XY:

940

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00723

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.00325

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.00897

GnomAD4 exome

AF:

0.00917

AC:

13396

AN:

1461132

Hom.:

Cov.:

AF XY:

0.00913

AC XY:

6640

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.00197

Gnomad4 AMR exome

AF:

0.00704

Gnomad4 ASJ exome

AF:

0.00995

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.00368

Gnomad4 NFE exome

AF:

0.0107

Gnomad4 OTH exome

AF:

0.00863

GnomAD4 genome

AF:

0.00643

AC:

979

AN:

152270

Hom.:

Cov.:

AF XY:

0.00587

AC XY:

437

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.00811

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.00995

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00879

Hom.:

Bravo

AF:

0.00685

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.0102

AC:

ExAC

AF:

0.00686

AC:

833

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00992

EpiControl

AF:

0.00960

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2022	Variant summary: BBS4 c.137A>G (p.Lys46Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0069 in 251304 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS4 causing Bardet-Biedl Syndrome phenotype (0.00069), strongly suggesting that the variant is benign. c.137A>G has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (example, Muller_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. One publication reports experimental evidence evaluating an impact on protein function and reports this as a null allele based on lack of ability to rescue bbs zebrafish morphants with human mRNA mutant construct, however, does not allow convincing conclusions about the variant effect (Zaghoul_2010). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as benign (n=4)/likely benign(n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 05, 2016	- -

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	BBS4: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 08, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2016	The K46R variant in the BBS4 gene was first reported as a likely non-disease causing variant (Mykytyn et al., 2003). In a more recent publication, Muller et al. (2010) identified K46R in the homozygous state in an individual diagnosed with Bardet-Biedl syndrome. A separate group performed functional studies in zebrafish by in vivo complementation analysis and predicted K46R is likely detrimental to the protein function (Zaghloul et al., 2010). However, K46R is reported as benign in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000229244.1; Landrum et al., 2015). The NHLBI ESP Exome Sequencing Project reports K46R was observed in 1.02% (88/8594) alleles from individuals of European American ancestry, indicating it may be a rare variant in this population. The K46R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K46R as a variant of uncertain significance. -

Bardet-Biedl syndrome 1

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Bardet-Biedl syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Bardet-Biedl syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;T

Eigen

Benign

-0.093

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0086

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

0.0050

B;.;.

Vest4

0.28

MVP

0.84

MPC

0.014

ClinPred

0.016

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.47

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