rs431905493

Positions:

• chr5-78985010-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000046.5(ARSB):​c.238del​(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 (★). 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.65

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 881.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.238del	p.Val80CysfsTer34	frameshift_variant	1/8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.238del	p.Val80CysfsTer34	frameshift_variant	1/8	1	NM_000046.5	ENSP00000264914	P1
ARSB	ENST00000396151.7	c.238del	p.Val80CysfsTer34	frameshift_variant	2/8	1		ENSP00000379455
ARSB	ENST00000565165.2	c.238del	p.Val80CysfsTer34	frameshift_variant	1/5	1		ENSP00000456339

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1381960 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 686722

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, type vi, severe Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1992

- -

Mucopolysaccharidosis type 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

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

Jan 01, 2018

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 v4.3

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

LitVar

Other links and lift over

dbSNP: rs431905493; hg19: chr5-78280833;