rs138744839

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024649.5(BBS1):c.235G>A(p.Glu79Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0012 in 1,614,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

BBS1
NM_024649.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 5.89

Variant links:

Genes affected

BBS1 (HGNC:966): (Bardet-Biedl syndrome 1) Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome. The encoded protein may play a role in eye, limb, cardiac and reproductive system development. [provided by RefSeq, Jul 2008]

BBS1 links:

ENSG00000256349 (HGNC:):

ENSG00000256349 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2314331).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS1	NM_024649.5 linkuse as main transcript	c.235G>A	p.Glu79Lys	missense_variant	4/17	ENST00000318312.12	NP_078925.3	Q8NFJ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS1	ENST00000318312.12 linkuse as main transcript	c.235G>A	p.Glu79Lys	missense_variant	4/17	1	NM_024649.5	ENSP00000317469.7		Q8NFJ9-1
ENSG00000256349	ENST00000419755.3 linkuse as main transcript	c.346G>A	p.Glu116Lys	missense_variant	4/17	2		ENSP00000398526.3

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

171

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000756

AC:

190

AN:

251320

Hom.:

AF XY:

0.000788

AC XY:

107

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00121

AC:

1774

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

828

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000831

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.00149

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.00112

AC:

170

AN:

152324

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00172

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00112

Hom.:

Bravo

AF:

0.000782

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000815

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 09, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 09, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 27, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 20, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 08, 2017

- -

BBS1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The BBS1 c.235G>A variant is predicted to result in the amino acid substitution p.Glu79Lys. This variant has been reported in two patients with primary ciliary dyskinesia and male infertility (Supp. Table 2, El Khouri et al. 2016. PubMed ID: 27486783), and one heterozygous patient with Retinitis pigmentosa (Table S1, Griffith. 2022. PubMed ID: 36011402). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Bardet-Biedl syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 79 of the BBS1 protein (p.Glu79Lys). This variant is present in population databases (rs138744839, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with BBS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 305458). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

.;D;D;D;.

Eigen

Benign

0.040

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

T;T;T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.23

T;T;T;T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

3.3

.;M;.;.;M

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.3

D;D;D;D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.0040

D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Polyphen

0.97, 0.97

.;D;.;D;.

Vest4

0.37

MVP

0.90

MPC

0.24

ClinPred

0.99

GERP RS

3.2

Varity_R

0.26

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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