chr5-78985010-AC-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000046.5(ARSB):c.238delG(p.Val80CysfsTer34) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000145 in 1,381,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V80V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ARSB
NM_000046.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.65

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 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-78985010-AC-A is Pathogenic according to our data. Variant chr5-78985010-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 881.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000046.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	NM_000046.5	MANE Select	c.238delG	p.Val80CysfsTer34	frameshift	Exon 1 of 8	NP_000037.2
	ARSB	NM_198709.3		c.238delG	p.Val80CysfsTer34	frameshift	Exon 2 of 8	NP_942002.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARSB	ENST00000264914.10	TSL:1 MANE Select	c.238delG	p.Val80CysfsTer34	frameshift	Exon 1 of 8	ENSP00000264914.4
ARSB	ENST00000396151.7	TSL:1	c.238delG	p.Val80CysfsTer34	frameshift	Exon 2 of 8	ENSP00000379455.3
ARSB	ENST00000565165.2	TSL:1	c.238delG	p.Val80CysfsTer34	frameshift	Exon 1 of 5	ENSP00000456339.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1381960

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28596

American (AMR)

AF:

0.00

AC:

AN:

35072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24056

East Asian (EAS)

AF:

0.00

AC:

AN:

31650

South Asian (SAS)

AF:

0.00

AC:

AN:

77606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4562

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1076208

Other (OTH)

AF:

0.00

AC:

AN:

56588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, type vi, severe

Pathogenic:1

Jan 01, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Mucopolysaccharidosis type 6

Pathogenic:1

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

Frameshift variant (PVS1); In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Absent from GnomAD (PM2); Reputable source identifies as pathogenic (PP5)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.6

Mutation Taster

=0/200

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over