rs781510986

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PM5PP2PP3PP5_Very_Strong

The ENST00000565165.2(ARSB):c.1144T>C(p.Tyr382His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,176 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y382N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ARSB
ENST00000565165.2 missense

Scores

Splicing: ADA: 0.9832

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.06

Publications

6 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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-78885582-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 559679.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: -0.77868 (below the threshold of 3.09). GenCC associations: The gene is linked to mucopolysaccharidosis type 6.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

PP5

Variant 5-78885582-A-G is Pathogenic according to our data. Variant chr5-78885582-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 559680.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.1142+2T>C		splice_donor_variant, intron_variant	Intron 5 of 7	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ARSB	ENST00000565165.2 link	c.1144T>C	p.Tyr382His	missense_variant	Exon 5 of 5	1		ENSP00000456339.2
ARSB	ENST00000264914.10 link	c.1142+2T>C		splice_donor_variant, intron_variant	Intron 5 of 7	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7 link	c.1142+2T>C		splice_donor_variant, intron_variant	Intron 6 of 7	1		ENSP00000379455.3
ARSB	ENST00000521800.2 link	n.324+2T>C		splice_donor_variant, intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000799

AC:

AN:

250232

AF XY:

0.0000148

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461176

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52756

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6

Pathogenic:2

Mar 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 5 of the ARSB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs781510986, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with mucopolysaccharidosis type VI (PMID: 23557332, 30524696). ClinVar contains an entry for this variant (Variation ID: 559680). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 33209960). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2018

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Splicing variant in canonical site (PVS1); In vitro functional studies supportive of a damaging effect on the gene product (demonstrated nonsense mediated RNA decay; PS3); Very low frequency in ExAC (PM2) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.94

PhyloP100

7.1

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.60

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: 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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over