rs773460207

chr5-78964517-G-Achr5-78964517-G-C

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.589C>T(p.Arg197Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,712 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ARSB NM_000046.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.935

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 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 5-78964517-G-A is Pathogenic according to our data. Variant chr5-78964517-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 559799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSB	NM_000046.5	c.589C>T	p.Arg197Ter	stop_gained	3/8	ENST00000264914.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSB	ENST00000264914.10	c.589C>T	p.Arg197Ter	stop_gained	3/8	1	NM_000046.5	P1
ARSB	ENST00000396151.7	c.589C>T	p.Arg197Ter	stop_gained	4/8	1
ARSB	ENST00000565165.2	c.589C>T	p.Arg197Ter	stop_gained	3/5	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 13, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	Nonsense 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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2020	Variant summary: ARSB c.589C>T (p.Arg197X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251310 control chromosomes. c.589C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome; Examples- Petry_2005, Dou_2006, Karageorgos_2007). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal ARSB enzymatic activity (examples- Dou_2006, Karageorgos_2007). One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Arg197*) 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: 16435196). ClinVar contains an entry for this variant (Variation ID: 559799). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.98
GERP RS		1.2

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: rs773460207; hg19: chr5-78260340; COSMIC: COSV99364609;