rs137853921

Positions:

chr2-169493769-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_152384.3(BBS5):c.551A>G(p.Asn184Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 1,612,686 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 21 hom. )

Consequence

BBS5
NM_152384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:6O:1

Conservation

PhyloP100: 9.32

Variant links:

Genes affected

BBS5 (HGNC:970): (Bardet-Biedl syndrome 5) This gene encodes a protein that has been directly linked to Bardet-Biedl syndrome. The primary features of this syndrome include retinal dystrophy, obesity, polydactyly, renal abnormalities and learning disabilities. Experimentation in non-human eukaryotes suggests that this gene is expressed in ciliated cells and that it is required for the formation of cilia. Alternate transcriptional splice variants have been observed but have not been fully characterized. [provided by RefSeq, Jul 2008]

BBS5 links:

ENSG00000251569 (HGNC:):

ENSG00000251569 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029099584).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00376 (572/152322) while in subpopulation NFE AF= 0.00635 (432/68030). AF 95% confidence interval is 0.00586. There are 2 homozygotes in gnomad4. There are 255 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS5	NM_152384.3 linkuse as main transcript	c.551A>G	p.Asn184Ser	missense_variant	7/12	ENST00000295240.8	NP_689597.1	Q8N3I7-1A0A0S2Z626

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS5	ENST00000295240.8 linkuse as main transcript	c.551A>G	p.Asn184Ser	missense_variant	7/12	1	NM_152384.3	ENSP00000295240.3		Q8N3I7-1
ENSG00000251569	ENST00000513963.1 linkuse as main transcript	c.551A>G	p.Asn184Ser	missense_variant	7/16	2		ENSP00000424363.1		E9PBE3

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00489

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00635

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00419

AC:

1053

AN:

251288

Hom.:

AF XY:

0.00426

AC XY:

579

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000817

Gnomad FIN exome

AF:

0.00480

Gnomad NFE exome

AF:

0.00698

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00520

AC:

7593

AN:

1460364

Hom.:

Cov.:

AF XY:

0.00519

AC XY:

3772

AN XY:

726556

show subpopulations

Gnomad4 AFR exome

AF:

0.000688

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00414

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000754

Gnomad4 FIN exome

AF:

0.00476

Gnomad4 NFE exome

AF:

0.00613

Gnomad4 OTH exome

AF:

0.00401

GnomAD4 genome

AF:

0.00376

AC:

572

AN:

152322

Hom.:

Cov.:

AF XY:

0.00342

AC XY:

255

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00489

Gnomad4 NFE

AF:

0.00635

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00593

Hom.:

Bravo

AF:

0.00346

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00438

AC:

532

Asia WGS

AF:

0.00116

AC:

AN:

3472

EpiCase

AF:

0.00616

EpiControl

AF:

0.00747

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	BBS5: PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2024	Reported previously in the heterozygous state in multiple individuals with a ciliopathy phenotype; however, these individuals harbored pathogenic variants in other genes which likely explained their phenotype, suggesting that N184S may either not contribute, or be a potentially modifying variant, to the phenotype (PMID: 24128419, 15137946, 23432027, 27486776, 31888296); Identified in a patient with cone-rod dystrophy who also harbored two other variants in BBS5, although phase of these variants was unknown (PMID: 28041643); Published functional studies demonstrated defects on developmental in zebrafish (PMID: 31506453); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29039417, 20498079, 15137946, 18203199, 22025579, 23432027, 28224992, 29068140, 31888296, 27486776, 32581362, 35835773, 34448047, 37240074, 31506453, 28041643, 24128419) -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2023	Variant summary: BBS5 c.551A>G (p.Asn184Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0042 in 251288 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 6.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS5 causing Bardet-Biedl Syndrome phenotype (0.00062), strongly suggesting that the variant is benign. The variant, c.551A>G, has been reported in the literature in individuals affected with Bardet-Biedl Syndrome, however in many cases it was found in heterozygous state, or together with other variants which could (potentially) explain the phenotype (e.g. Li_2004, Zaghoul_2010, Castro-Sanchez_2019, and the LOVD database). These reports do not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. Publications reported experimental evidence evaluating an impact on protein and demonstrated developmental defects in zebrafish embryos (Zaghoul_2010, Castro-Sanchez_2019), however, these assays do not allow convincing conclusions about the variant effect humans. Five submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as likely pathogenic (n=1), VUS (n=1), likely benign (n=2) / benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 18, 2018	- -

Cone dystrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Bardet-Biedl syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.0

M;M;.

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.93

MVP

0.94

MPC

0.96

ClinPred

0.038

GERP RS

6.0

Varity_R

0.72

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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