dbSNP rs1554032134: ARSB:p.Val80TrpfsTer32 (chr5-78985005-GGAGCACC-G) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000046.5(ARSB):c.237_243delGGTGCTC(p.Val80TrpfsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

ARSB
NM_000046.5 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 8.80

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

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

PP5

Variant 5-78985005-GGAGCACC-G is Pathogenic according to our data. Variant chr5-78985005-GGAGCACC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559744.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.237_243delGGTGCTC	p.Val80TrpfsTer32	frameshift_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.237_243delGGTGCTC	p.Val80TrpfsTer32	frameshift_variant	Exon 1 of 8	1	NM_000046.5	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7 link	c.237_243delGGTGCTC	p.Val80TrpfsTer32	frameshift_variant	Exon 2 of 8	1		ENSP00000379455.3	P15848-2
ARSB	ENST00000565165.2 link	c.237_243delGGTGCTC	p.Val80TrpfsTer32	frameshift_variant	Exon 1 of 5	1		ENSP00000456339.2	A0A2U3U034
ARSB	ENST00000521117.1 link	c.100_106delGGTGCTC		downstream_gene_variant		3		ENSP00000428611.1	E5RHC4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151828

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151934

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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

May 31, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val80Trpfs*32) in the ARSB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSB are known to be pathogenic (PMID: 17458871, 22133300). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 8125475). ClinVar contains an entry for this variant (Variation ID: 559744). 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: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Frameshift variant(PVS1); Absent from GnomAD (PM2) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over