NM_000046.5:c.194C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000046.5(ARSB):c.194C>T(p.Ser65Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S65S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARSB
NM_000046.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.49

Publications

5 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: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000046.5

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 5-78985055-G-A is Pathogenic according to our data. Variant chr5-78985055-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 559735.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5 link	c.194C>T	p.Ser65Phe	missense_variant	Exon 1 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.194C>T	p.Ser65Phe	missense_variant	Exon 1 of 8	1	NM_000046.5	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7 link	c.194C>T	p.Ser65Phe	missense_variant	Exon 2 of 8	1		ENSP00000379455.3	P15848-2
ARSB	ENST00000565165.2 link	c.194C>T	p.Ser65Phe	missense_variant	Exon 1 of 5	1		ENSP00000456339.2	A0A2U3U034
ARSB	ENST00000521117.1 link	c.*57C>T		downstream_gene_variant		3		ENSP00000428611.1	E5RHC4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1389956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690972

African (AFR)

AF:

0.00

AC:

AN:

28788

American (AMR)

AF:

0.00

AC:

AN:

36328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24222

East Asian (EAS)

AF:

0.00

AC:

AN:

32256

South Asian (SAS)

AF:

0.00

AC:

AN:

78494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5208

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078096

Other (OTH)

AF:

0.00

AC:

AN:

56870

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6

Pathogenic:1Uncertain:1

Jan 01, 2018

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Absent from GnomAD (PM2); -

Feb 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ARSB c.194C>T (p.Ser65Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182476 control chromosomes (gnomAD). c.194C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome; e.g. Villani_1999, Voskoboeva_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10036316, 35118118). ClinVar contains an entry for this variant (Variation ID: 559735). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M;.

PhyloP100

7.5

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.73

MutPred

0.86

Loss of disorder (P = 0.0652);Loss of disorder (P = 0.0652);Loss of disorder (P = 0.0652);

MVP

0.99

MPC

0.91

ClinPred

1.0

GERP RS

3.6

PromoterAI

0.22

Neutral

(source)

Varity_R

0.95

gMVP

0.94

Mutation Taster

=13/87

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over