rs25414

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000046.5(ARSB):c.1151G>A(p.Ser384Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0532 in 1,612,922 control chromosomes in the GnomAD database, including 2,646 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S384S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.039 ( 162 hom., cov: 32)

Exomes 𝑓: 0.055 ( 2484 hom. )

Consequence

ARSB
NM_000046.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.528

Publications

35 publications found

Variant links:

Genes affected

ARSB (HGNC:714): (arylsulfatase B) Arylsulfatase B encoded by this gene belongs to the sulfatase family. The arylsulfatase B homodimer hydrolyzes sulfate groups of N-Acetyl-D-galactosamine, chondriotin sulfate, and dermatan sulfate. The protein is targeted to the lysozyme. Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Dec 2016]

ARSB Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 6
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Illumina, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ARSB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000046.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 85 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 0.63089 (below the threshold of 3.09). Trascript score misZ: -0.06109 (below the threshold of 3.09). GenCC associations: The gene is linked to mucopolysaccharidosis type 6.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047851205).

BP6

Variant 5-78839418-C-T is Benign according to our data. Variant chr5-78839418-C-T is described in ClinVar as Benign. ClinVar VariationId is 92352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5 link	c.1151G>A	p.Ser384Asn	missense_variant	Exon 6 of 8	ENST00000264914.10	NP_000037.2	P15848-1A0A024RAJ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10 link	c.1151G>A	p.Ser384Asn	missense_variant	Exon 6 of 8	1	NM_000046.5	ENSP00000264914.4		P15848-1
ARSB	ENST00000396151.7 link	c.1151G>A	p.Ser384Asn	missense_variant	Exon 7 of 8	1		ENSP00000379455.3		P15848-2

Frequencies

GnomAD3 genomes

AF:

0.0395

AC:

6013

AN:

152090

Hom.:

162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0417

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0426

Gnomad FIN

AF:

0.0411

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0608

Gnomad OTH

AF:

0.0326

GnomAD2 exomes

AF:

0.0425

AC:

10688

AN:

251314

AF XY:

0.0434

show subpopulations

Gnomad AFR exome

AF:

0.00984

Gnomad AMR exome

AF:

0.0391

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0446

Gnomad NFE exome

AF:

0.0565

Gnomad OTH exome

AF:

0.0448

GnomAD4 exome

AF:

0.0546

AC:

79748

AN:

1460714

Hom.:

2484

Cov.:

AF XY:

0.0543

AC XY:

39429

AN XY:

726678

show subpopulations

African (AFR)

AF:

0.00864

AC:

289

AN:

33448

American (AMR)

AF:

0.0385

AC:

1719

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

481

AN:

26114

East Asian (EAS)

AF:

0.000126

AC:

AN:

39674

South Asian (SAS)

AF:

0.0443

AC:

3819

AN:

86250

European-Finnish (FIN)

AF:

0.0442

AC:

2360

AN:

53376

Middle Eastern (MID)

AF:

0.0295

AC:

170

AN:

5764

European-Non Finnish (NFE)

AF:

0.0612

AC:

67961

AN:

1111080

Other (OTH)

AF:

0.0488

AC:

2944

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

3524

7048

10571

14095

17619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2496

4992

7488

9984

12480

<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:

0.0395

AC:

6012

AN:

152208

Hom.:

162

Cov.:

AF XY:

0.0377

AC XY:

2805

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0109

AC:

454

AN:

41550

American (AMR)

AF:

0.0418

AC:

639

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5190

South Asian (SAS)

AF:

0.0427

AC:

205

AN:

4806

European-Finnish (FIN)

AF:

0.0411

AC:

436

AN:

10598

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0608

AC:

4131

AN:

67988

Other (OTH)

AF:

0.0318

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

287

573

860

1146

1433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0489

Hom.:

588

Bravo

AF:

0.0359

TwinsUK

AF:

0.0583

AC:

216

ALSPAC

AF:

0.0701

AC:

270

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.0627

AC:

539

ExAC

AF:

0.0424

AC:

5149

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0530

EpiControl

AF:

0.0529

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6

Benign:5

Mar 06, 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. -

Jan 01, 2018

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

Allele frequency greater than expected for disorder (BS1); Homozygotes reported in ExAC (BS2); Classified benign by a reputable source (BP6) -

Nov 05, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign, for Mucopolysaccharidosis type VI, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS4 => Lack of segregation in affected members of a family (PMID:19259130). -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Jul 13, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19259130, 11668612, 16435196, 18406185, 20981092, 20220177, 23557332, 21228398, 27884173, 28552677) -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.6

L;L

PhyloP100

0.53

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.73

N;N

REVEL

Benign

0.26

Sift

Benign

0.43

T;T

Sift4G

Benign

0.49

T;T

Polyphen

0.0070

B;.

Vest4

0.066

MPC

0.22

ClinPred

0.0098

GERP RS

4.0

Varity_R

0.10

gMVP

0.62

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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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