rs1554032243

Positions:

• chr5-78985125-TGGCCCCGG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000046.5(ARSB):​c.116_123delCCGGGGCC​(p.Ala39fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSB NM_000046.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.28

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 5-78985125-TGGCCCCGG-T is Pathogenic according to our data. Variant chr5-78985125-TGGCCCCGG-T is described in ClinVar as [Pathogenic]. Clinvar id is 495377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.116_123delCCGGGGCC	p.Ala39fs	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.116_123delCCGGGGCC	p.Ala39fs	frameshift_variant	1/8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.116_123delCCGGGGCC	p.Ala39fs	frameshift_variant	2/8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.116_123delCCGGGGCC	p.Ala39fs	frameshift_variant	1/5	1		ENSP00000456339.2
ARSB	ENST00000521117.1	c.116_123delCCGGGGCC	p.Ala39fs	frameshift_variant	2/2	3		ENSP00000428611.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:3

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) -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2016	Variant summary: The ARSB c.116_123delCCGGGGCC (p.Ala39Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent ARSB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar (e.g.c.238delG/p.Val80Cysfs). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in at least one MPS6 patient without detectable ARSB protein or activity. The variant is absent in 38156 control chromosomes. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554032243; hg19: chr5-78280948;