NM_024649.5:c.378G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_024649.5(BBS1):c.378G>A(p.Leu126Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,210 control chromosomes in the GnomAD database, including 45,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3877 hom., cov: 32)

Exomes 𝑓: 0.24 ( 42057 hom. )

Consequence

BBS1
NM_024649.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.14

Publications

31 publications found

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 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS1 links:

ENSG00000256349 (HGNC:):

ENSG00000256349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.137).

BP6

Variant 11-66514624-G-A is Benign according to our data. Variant chr11-66514624-G-A is described in ClinVar as Benign. ClinVar VariationId is 261750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS1	NM_024649.5 link	c.378G>A	p.Leu126Leu	synonymous_variant	Exon 4 of 17	ENST00000318312.12	NP_078925.3	Q8NFJ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS1	ENST00000318312.12 link	c.378G>A	p.Leu126Leu	synonymous_variant	Exon 4 of 17	1	NM_024649.5	ENSP00000317469.7		Q8NFJ9-1
ENSG00000256349	ENST00000419755.3 link	c.489G>A	p.Leu163Leu	synonymous_variant	Exon 4 of 17	2		ENSP00000398526.3

Frequencies

GnomAD3 genomes

AF:

0.212

AC:

32259

AN:

151952

Hom.:

3870

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.257

Gnomad AMR

AF:

0.169

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.268

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.387

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.179

GnomAD2 exomes

AF:

0.224

AC:

56195

AN:

250730

AF XY:

0.227

show subpopulations

Gnomad AFR exome

AF:

0.130

Gnomad AMR exome

AF:

0.141

Gnomad ASJ exome

AF:

0.168

Gnomad EAS exome

AF:

0.269

Gnomad FIN exome

AF:

0.379

Gnomad NFE exome

AF:

0.237

Gnomad OTH exome

AF:

0.210

GnomAD4 exome

AF:

0.235

AC:

344006

AN:

1461140

Hom.:

42057

Cov.:

AF XY:

0.236

AC XY:

171356

AN XY:

726920

show subpopulations

African (AFR)

AF:

0.126

AC:

4208

AN:

33480

American (AMR)

AF:

0.144

AC:

6421

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

4382

AN:

26134

East Asian (EAS)

AF:

0.261

AC:

10358

AN:

39698

South Asian (SAS)

AF:

0.215

AC:

18517

AN:

86254

European-Finnish (FIN)

AF:

0.372

AC:

19659

AN:

52810

Middle Eastern (MID)

AF:

0.132

AC:

761

AN:

5768

European-Non Finnish (NFE)

AF:

0.240

AC:

266365

AN:

1111896

Other (OTH)

AF:

0.221

AC:

13335

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

14677

29354

44031

58708

73385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9002

18004

27006

36008

45010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.212

AC:

32278

AN:

152070

Hom.:

3877

Cov.:

AF XY:

0.217

AC XY:

16144

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.135

AC:

5613

AN:

41490

American (AMR)

AF:

0.170

AC:

2600

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

522

AN:

3468

East Asian (EAS)

AF:

0.268

AC:

1383

AN:

5160

South Asian (SAS)

AF:

0.202

AC:

976

AN:

4824

European-Finnish (FIN)

AF:

0.387

AC:

4083

AN:

10554

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.242

AC:

16457

AN:

67974

Other (OTH)

AF:

0.176

AC:

372

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1269

2538

3808

5077

6346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.219

Hom.:

7199

Bravo

AF:

0.191

Asia WGS

AF:

0.239

AC:

831

AN:

3478

EpiCase

AF:

0.222

EpiControl

AF:

0.228

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 1

Benign:6

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 15, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The BBS1 c.378G>A (p.Leu126Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a polymorphism outcome for this variant along with 5/5 splice prediction tools predicting the variant not to have an impact on normal splicing. This variant was found in 27024/121032 control chromosomes (3285 homozygotes) at a frequency of 0.2232798, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic BBS1 variant (0.0009449), suggesting this variant is likely a benign polymorphism. A clinical diagnostic laboratory and at least one publication classified this variant as benign. Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

1.1

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over