rs137853921

Variant names:

• chr2-169493769-A-G
• rs137853921
• NM_152384.3:c.551A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:6 O:1
• Conservation: PhyloP100: 9.32

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]

ENSG00000251569 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
BBS5	NM_152384.3	c.551A>G	p.Asn184Ser	missense_variant	Exon 7 of 12	ENST00000295240.8	NP_689597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS5	ENST00000295240.8	c.551A>G	p.Asn184Ser	missense_variant	Exon 7 of 12	1	NM_152384.3	ENSP00000295240.3
ENSG00000251569	ENST00000513963.1	c.551A>G	p.Asn184Ser	missense_variant	Exon 7 of 16	2		ENSP00000424363.1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152204 Hom.: 2 Cov.: 32

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.: 2 AF XY: 0.00426 AC XY: 579 AN XY: 135832

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.: 21 Cov.: 29 AF XY: 0.00519 AC XY: 3772 AN XY: 726556

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.: 2 Cov.: 32 AF XY: 0.00342 AC XY: 255 AN XY: 74488

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.: 5

Bravo AF: 0.00346

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00438 AC: 532

Asia WGS AF: 0.00116 AC: 4 AN: 3472

EpiCase AF: 0.00616

EpiControl AF: 0.00747

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2 Other:1

-

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 22, 2017

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BBS5: PP3, BS2 -

not specified Benign:3

Apr 07, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2023

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: 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. -

Cone dystrophy Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Retinal dystrophy Uncertain:1

Jan 01, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome Benign:1

Feb 03, 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	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Uncertain	0.49	D
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	T
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

Other links and lift over

dbSNP: rs137853921; hg19: chr2-170350279; COSMIC: COSV104598691; COSMIC: COSV104598691;