chr15-72709760-A-G

Variant names:

• chr15-72709760-A-G
• rs75295839
• NM_033028.5:c.137A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 13/21 in silico tools predict 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. K46K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (94 hom.)
• Consequence: BBS4 NM_033028.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 6.34
• Publications: 12 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 196570.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS4	NM_033028.5	c.137A>G	p.Lys46Arg	missense_variant	Exon 3 of 16	ENST00000268057.9	NP_149017.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS4	ENST00000268057.9	c.137A>G	p.Lys46Arg	missense_variant	Exon 3 of 16	1	NM_033028.5	ENSP00000268057.4

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 979 AN: 152152 Hom.: 3 Cov.: 32

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

GnomAD2 exomes AF: 0.00687 AC: 1726 AN: 251304 AF XY: 0.00692

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 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.: 94 Cov.: 32 AF XY: 0.00913 AC XY: 6640 AN XY: 726924

African (AFR) AF: 0.00197 AC: 66 AN: 33466

American (AMR) AF: 0.00704 AC: 315 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00995 AC: 260 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86252

European-Finnish (FIN) AF: 0.00368 AC: 196 AN: 53254

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5764

European-Non Finnish (NFE) AF: 0.0107 AC: 11908 AN: 1111490

Other (OTH) AF: 0.00863 AC: 521 AN: 60376

GnomAD4 genome AF: 0.00643 AC: 979 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74458

African (AFR) AF: 0.00207 AC: 86 AN: 41530

American (AMR) AF: 0.00811 AC: 124 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00995 AC: 677 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00881 Hom.: 31

Bravo AF: 0.00685

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00686 AC: 833

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00992

EpiControl AF: 0.00960

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Jan 11, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 12, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely 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 Uncertain:1 Benign:3

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BBS4: BS1, BS2 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 08, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bardet-Biedl syndrome 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 29, 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	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;T
Eigen	Benign	-0.093
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;D
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;.;.
PhyloP100		6.3
PrimateAI	Uncertain	0.58	T
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	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.47
Mutation Taster		=256/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs75295839; hg19: chr15-73002101;