rs118203942

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000046.5(ARSB):c.284G>T(p.Arg95Leu) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95Q) has been classified as Likely pathogenic.

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

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.73

Publications

0 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 13 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000046.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-78984965-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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, 0.98

PP5

Variant 5-78984965-C-A is Pathogenic according to our data. Variant chr5-78984965-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1465582.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5 link	c.284G>T	p.Arg95Leu	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.284G>T	p.Arg95Leu	missense_variant	Exon 1 of 8	1	NM_000046.5	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7 link	c.284G>T	p.Arg95Leu	missense_variant	Exon 2 of 8	1		ENSP00000379455.3	P15848-2
ARSB	ENST00000565165.2 link	c.284G>T	p.Arg95Leu	missense_variant	Exon 1 of 5	1		ENSP00000456339.2	A0A2U3U034
ARSB	ENST00000521117.1 link	c.*147G>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:

1336738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

662560

African (AFR)

AF:

0.00

AC:

AN:

28076

American (AMR)

AF:

0.00

AC:

AN:

31924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23078

East Asian (EAS)

AF:

0.00

AC:

AN:

30590

South Asian (SAS)

AF:

0.00

AC:

AN:

70280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4092

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1051200

Other (OTH)

AF:

0.00

AC:

AN:

54264

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6

Pathogenic:1

Oct 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with ARSB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 95 of the ARSB protein (p.Arg95Leu). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg95 amino acid residue in ARSB. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.66

BayesDel_noAF

Pathogenic

0.71

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

H;H;.

PhyloP100

5.7

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.4

D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.94

MutPred

0.85

Loss of catalytic residue at R95 (P = 0.0247);Loss of catalytic residue at R95 (P = 0.0247);Loss of catalytic residue at R95 (P = 0.0247);

MVP

0.99

MPC

0.97

ClinPred

1.0

GERP RS

4.6

PromoterAI

-0.0018

Neutral

(source)

Varity_R

0.99

gMVP

0.99

Mutation Taster

=2/98

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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