rs1236509896

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_000046.5(ARSB):c.175G>A(p.Asp59Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,391,952 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D59G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ARSB
NM_000046.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.67

Publications

2 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 11 ACMG points.

PM1

In a hotspot region, there are 10 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-78985073-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 559734.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, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5 link	c.175G>A	p.Asp59Asn	missense_variant	Exon 1 of 8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ARSB	ENST00000264914.10 link	c.175G>A	p.Asp59Asn	missense_variant	Exon 1 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7 link	c.175G>A	p.Asp59Asn	missense_variant	Exon 2 of 8	1		ENSP00000379455.3
ARSB	ENST00000565165.2 link	c.175G>A	p.Asp59Asn	missense_variant	Exon 1 of 5	1		ENSP00000456339.2
ARSB	ENST00000521117.1 link	c.*38G>A		downstream_gene_variant		3		ENSP00000428611.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1391952

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

691800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28768

American (AMR)

AF:

0.00

AC:

AN:

36640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24252

East Asian (EAS)

AF:

0.00

AC:

AN:

32420

South Asian (SAS)

AF:

0.0000254

AC:

AN:

78732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49718

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5192

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079226

Other (OTH)

AF:

0.00

AC:

AN:

57004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 11, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ARSB c.175G>A (p.Asp59Asn) results in a conservative amino acid change located in the sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182070 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.175G>A has been reported in the literature in the heterozygous state in two Brazilian individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (Petry_2005, Horovitz_2015). These reports do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28649537, 16435196). One submitter has provided a clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Mucopolysaccharidosis type 6

Uncertain: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);

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M;.

PhyloP100

5.7

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.89

ClinPred

1.0

GERP RS

4.4

PromoterAI

0.0012

Neutral

(source)

Varity_R

0.98

gMVP

0.97

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

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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