rs2277598

Positions:

• chr15-72735137-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.248

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a repeat TPR 9 (size 32) in uniprot entity BBS4_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) 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/exons	MANE	UniProt
BBS4	NM_033028.5	c.1061T>C	p.Ile354Thr	missense_variant	13/16	ENST00000268057.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS4	ENST00000268057.9	c.1061T>C	p.Ile354Thr	missense_variant	13/16	1	NM_033028.5	P1

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80060 AN: 151870 Hom.: 23108 Cov.: 32

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

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.: 37 AF XY: 0.616 AC XY: 447589 AN XY: 726432

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.: 32 AF XY: 0.530 AC XY: 39337 AN XY: 74266

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Bardet-Biedl syndrome 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, no assertion criteria provided	curation	GeneReviews	Oct 13, 2009	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Bardet-Biedl syndrome 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

literature only

Department of Ophthalmology and Visual Sciences Kyoto University

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.3
DANN	Benign	0.66
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.12	T;T
MetaRNN	Benign	0.0000021	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.22	T
REVEL	Benign	0.19
Sift4G	Benign	0.40	T;T
Polyphen		0.0	.;B
Vest4		0.066
MPC		0.012
ClinPred		0.0091	T
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

Other links and lift over

dbSNP: rs2277598; hg19: chr15-73027478; COSMIC: COSV51438920; COSMIC: COSV51438920;