GeneBe

rs367650121

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_000046.5(ARSB):ā€‹c.667A>Gā€‹(p.Ile223Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000072 ( 0 hom., cov: 33)
Exomes š‘“: 0.000044 ( 0 hom. )

Consequence

ARSB
NM_000046.5 missense

Scores

6
5
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 5.55
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.771
PP5
Variant 5-78964439-T-C is Pathogenic according to our data. Variant chr5-78964439-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 559803.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARSBNM_000046.5 linkc.667A>G p.Ile223Val missense_variant Exon 3 of 8 ENST00000264914.10 NP_000037.2 P15848-1A0A024RAJ9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARSBENST00000264914.10 linkc.667A>G p.Ile223Val missense_variant Exon 3 of 8 1 NM_000046.5 ENSP00000264914.4 P15848-1
ARSBENST00000396151.7 linkc.667A>G p.Ile223Val missense_variant Exon 4 of 8 1 ENSP00000379455.3 P15848-2
ARSBENST00000565165.2 linkc.667A>G p.Ile223Val missense_variant Exon 3 of 5 1 ENSP00000456339.2 A0A2U3U034

Frequencies

GnomAD3 genomes
AF:
0.0000722
AC:
11
AN:
152254
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251246
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135790
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000445
AC:
65
AN:
1461686
Hom.:
0
Cov.:
31
AF XY:
0.0000468
AC XY:
34
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000540
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152254
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000575
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.000218
EpiControl
AF:
0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:4Uncertain:2
Aug 25, 2022
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 28, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 27, 2024
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2018
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in GnomAD (PM2) -

Mar 18, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ARSB c.667A>G (p.Ile223Val) results in a conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251246 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ARSB causing Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (6e-05 vs 0.0022), allowing no conclusion about variant significance. c.667A>G has been reported in the literature in at least one homozygous individual affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome, Karageorgos_2007). These data indicate that the variant may be associated with disease. Fibroblasts from this homozygous patient had reduced ARSB protein expression and undetectable ARSB activity (Karageorgos_2007). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jul 04, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 223 of the ARSB protein (p.Ile223Val). This variant is present in population databases (rs367650121, gnomAD 0.01%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17458871). ClinVar contains an entry for this variant (Variation ID: 559803). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSB protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.29
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.71
D;.;.
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.80
T;T;T
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.77
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.1
L;L;.
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-0.79
N;N;N
REVEL
Pathogenic
0.69
Sift
Benign
0.090
T;T;T
Sift4G
Benign
0.13
T;T;T
Polyphen
0.57
P;.;.
Vest4
0.78
MVP
0.77
MPC
0.34
ClinPred
0.20
T
GERP RS
5.4
Varity_R
0.28
gMVP
0.78

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.

Other links and lift over

dbSNP: rs367650121; hg19: chr5-78260262; API