NM_000046.5:c.1126G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000046.5(ARSB):c.1126G>A(p.Val376Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,613,742 control chromosomes in the GnomAD database, including 22,375 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1673 hom., cov: 32)

Exomes 𝑓: 0.16 ( 20702 hom. )

Consequence

ARSB
NM_000046.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.24

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023964942).

BP6

Variant 5-78885600-C-T is Benign according to our data. Variant chr5-78885600-C-T is described in ClinVar as [Benign]. Clinvar id is 92351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78885600-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5 link	c.1126G>A	p.Val376Met	missense_variant	Exon 5 of 8	ENST00000264914.10	NP_000037.2	P15848-1A0A024RAJ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARSB	ENST00000264914.10 link	c.1126G>A	p.Val376Met	missense_variant	Exon 5 of 8	1	NM_000046.5	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7 link	c.1126G>A	p.Val376Met	missense_variant	Exon 6 of 8	1		ENSP00000379455.3	P15848-2
ARSB	ENST00000565165.2 link	c.1126G>A	p.Val376Met	missense_variant	Exon 5 of 5	1		ENSP00000456339.2	A0A2U3U034
ARSB	ENST00000521800.2 link	n.308G>A		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20560

AN:

151988

Hom.:

1671

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0669

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.0158

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.172

GnomAD3 exomes

AF:

0.153

AC:

38291

AN:

250944

Hom.:

3350

AF XY:

0.155

AC XY:

21092

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.0633

Gnomad AMR exome

AF:

0.204

Gnomad ASJ exome

AF:

0.241

Gnomad EAS exome

AF:

0.0141

Gnomad SAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.163

Gnomad OTH exome

AF:

0.166

GnomAD4 exome

AF:

0.163

AC:

237977

AN:

1461636

Hom.:

20702

Cov.:

AF XY:

0.164

AC XY:

119573

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.0636

Gnomad4 AMR exome

AF:

0.205

Gnomad4 ASJ exome

AF:

0.245

Gnomad4 EAS exome

AF:

0.00824

Gnomad4 SAS exome

AF:

0.182

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.168

Gnomad4 OTH exome

AF:

0.162

GnomAD4 genome

AF:

0.135

AC:

20568

AN:

152106

Hom.:

1673

Cov.:

AF XY:

0.134

AC XY:

9990

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0667

Gnomad4 AMR

AF:

0.189

Gnomad4 ASJ

AF:

0.255

Gnomad4 EAS

AF:

0.0158

Gnomad4 SAS

AF:

0.189

Gnomad4 FIN

AF:

0.113

Gnomad4 NFE

AF:

0.165

Gnomad4 OTH

AF:

0.169

Alfa

AF:

0.158

Hom.:

3237

Bravo

AF:

0.137

TwinsUK

AF:

0.172

AC:

638

ALSPAC

AF:

0.172

AC:

661

ESP6500AA

AF:

0.0701

AC:

309

ESP6500EA

AF:

0.171

AC:

1473

ExAC

AF:

0.146

AC:

17767

Asia WGS

AF:

0.118

AC:

413

AN:

3478

EpiCase

AF:

0.169

EpiControl

AF:

0.168

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 19, 2014

Eurofins Ntd Llc (ga)

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

- -

Mucopolysaccharidosis type 6

Benign:3

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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. -

not provided

Benign:2

Oct 22, 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

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

T;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.73

T;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.9

L;L;.

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.2

N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.83

P;.;.

Vest4

0.060

MPC

0.37

ClinPred

0.011

GERP RS

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.074

gMVP

0.81

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

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