rs758139447

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024649.5(BBS1):c.1139G>A(p.Arg380Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

BBS1
NM_024649.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 7.93

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:

ZDHHC24 (HGNC:27387): (zinc finger DHHC-type containing 24) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Predicted to be involved in peptidyl-L-cysteine S-palmitoylation and protein targeting to membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ZDHHC24 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS1	NM_024649.5 linkuse as main transcript	c.1139G>A	p.Arg380Gln	missense_variant	12/17	ENST00000318312.12	NP_078925.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS1	ENST00000318312.12 linkuse as main transcript	c.1139G>A	p.Arg380Gln	missense_variant	12/17	1	NM_024649.5	ENSP00000317469	P1	Q8NFJ9-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251472

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 02, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 31, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 30, 2019	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	Dec 30, 2021	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27434533) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	BBS1: PM2:Supporting -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 05, 2022

Variant summary: BBS1 c.1139G>A (p.Arg380Gln) 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 2e-05 in 251472 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1139G>A has been reported in the literature in one individual affected with Joubert syndrome without co-segregation evidence. This report does not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Bardet-Biedl syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 380 of the BBS1 protein (p.Arg380Gln). This variant is present in population databases (rs758139447, gnomAD 0.02%). This missense change has been observed in individual(s) with BBS1-related conditions (PMID: 27434533). ClinVar contains an entry for this variant (Variation ID: 216740). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BBS1 protein function. 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

0.12

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

.;D;T;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

2.0

.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.5

N;N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.14

T;D;D;T

Sift4G

Uncertain

0.010

D;D;D;T

Polyphen

1.0, 1.0

.;D;D;.

Vest4

0.68

MutPred

0.88

.;Loss of methylation at R380 (P = 0.0602);.;.;

MVP

0.97

MPC

0.70

ClinPred

0.87

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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