rs1554032217

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000046.5(ARSB):c.157G>A(p.Asp53Asn) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D53G) 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

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.38

Publications

1 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 19 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr5-78985091-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1517883.Status of the report is criteria_provided_single_submitter, 1 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, 0.99

PP5

Variant 5-78985092-C-T is Pathogenic according to our data. Variant chr5-78985092-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 559725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5 link	c.157G>A	p.Asp53Asn	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.157G>A	p.Asp53Asn	missense_variant	Exon 1 of 8	1	NM_000046.5	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7 link	c.157G>A	p.Asp53Asn	missense_variant	Exon 2 of 8	1		ENSP00000379455.3	P15848-2
ARSB	ENST00000565165.2 link	c.157G>A	p.Asp53Asn	missense_variant	Exon 1 of 5	1		ENSP00000456339.2	A0A2U3U034
ARSB	ENST00000521117.1 link	c.*20G>A		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:

1376298

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

681984

African (AFR)

AF:

0.00

AC:

AN:

28528

American (AMR)

AF:

0.00

AC:

AN:

35448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23986

East Asian (EAS)

AF:

0.00

AC:

AN:

31884

South Asian (SAS)

AF:

0.00

AC:

AN:

77096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5148

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1069028

Other (OTH)

AF:

0.00

AC:

AN:

56146

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6

Pathogenic:3

Dec 24, 2022

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense variation in exon 1 of ARSB gene that results in amino acid substitution of Aspargine for Aspartic acid at codon 53 was detected. The observed variant c.157G>A (p.Asp53Asn) has not been reported in the 1000 genomes and gnomAD databases. The in-silico predictions for the variant is disease causing by MutationTaster2, SIFT and PROVEAN. In summary, the variant is pathogenic. -

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);Located in a well-established functional domain (PM1); Absent from GnomAD (PM2); Multiple lines of computational evidence support a deleterious effect on the gene product (PP3); -

Jun 08, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.7

H;H;.

PhyloP100

7.4

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.97

MutPred

0.92

Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);

MVP

0.98

MPC

2.8

ClinPred

1.0

GERP RS

4.3

PromoterAI

-0.00020

Neutral

(source)

Varity_R

0.99

gMVP

0.99

Mutation Taster

=3/97

disease causing (ClinVar)

(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