rs25414

chr5-78839418-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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 (★★). 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.528

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000046.5
• 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	UniProt
ARSB	NM_000046.5	c.1151G>A	p.Ser384Asn	missense_variant	6/8	ENST00000264914.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSB	ENST00000264914.10	c.1151G>A	p.Ser384Asn	missense_variant	6/8	1	NM_000046.5	P1
ARSB	ENST00000396151.7	c.1151G>A	p.Ser384Asn	missense_variant	7/8	1

Frequencies

GnomAD3 genomes AF: 0.0395 AC: 6013 AN: 152090 Hom.: 162 Cov.: 32

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

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.: 33 AF XY: 0.0543 AC XY: 39429 AN XY: 726678

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.: 32 AF XY: 0.0377 AC XY: 2805 AN XY: 74408

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: 55

ESP6500EA AF: 0.0627 AC: 539

ExAC AF: 0.0424 AC: 5149

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.0530

EpiControl AF: 0.0529

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 05, 2019	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	15
Dann	Benign	0.95
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.34	T
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	T
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

Other links and lift over

dbSNP: rs25414; hg19: chr5-78135241; COSMIC: COSV53724705;