rs25414

Positions:

chr5-78839418-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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=0.0047851205).

BP6

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

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/exons	MANE	Protein	UniProt
ARSB	NM_000046.5 link	c.1151G>A	p.Ser384Asn	missense_variant	6/8	ENST00000264914.10	NP_000037.2	P15848-1A0A024RAJ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10 link	c.1151G>A	p.Ser384Asn	missense_variant	6/8	1	NM_000046.5	ENSP00000264914.4		P15848-1
ARSB	ENST00000396151.7 link	c.1151G>A	p.Ser384Asn	missense_variant	7/8	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

GnomAD3 exomes

AF:

0.0425

AC:

10688

AN:

251314

Hom.:

280

AF XY:

0.0434

AC XY:

5889

AN XY:

135812

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 SAS exome

AF:

0.0432

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

Gnomad4 AFR exome

AF:

0.00864

Gnomad4 AMR exome

AF:

0.0385

Gnomad4 ASJ exome

AF:

0.0184

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0443

Gnomad4 FIN exome

AF:

0.0442

Gnomad4 NFE exome

AF:

0.0612

Gnomad4 OTH exome

AF:

0.0488

GnomAD4 genome

AF:

0.0395

AC:

6012

AN:

152208

Hom.:

162

Cov.:

AF XY:

0.0377

AC XY:

2805

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0109

Gnomad4 AMR

AF:

0.0418

Gnomad4 ASJ

AF:

0.0176

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0427

Gnomad4 FIN

AF:

0.0411

Gnomad4 NFE

AF:

0.0608

Gnomad4 OTH

AF:

0.0318

Alfa

AF:

0.0509

Hom.:

468

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 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. -
Benign, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	Allele frequency greater than expected for disorder (BS1); Homozygotes reported in ExAC (BS2); Classified benign by a reputable source (BP6) -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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). -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 19259130, 11668612, 16435196, 18406185, 20981092, 20220177, 23557332, 21228398, 27884173, 28552677) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -

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

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

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

Splicing

Name

Calibrated prediction

Score

Prediction

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

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