rs1554069655

Positions:

• chr5-78780398-T-C
• chr5-78780398-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_000046.5(ARSB):​c.1601A>G​(p.Ter534Trpext*?) variant causes a stop lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARSB NM_000046.5 stop_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 6.53

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000046.5 Downstream stopcodon found after 127 codons.
• PP5: Variant 5-78780398-T-C is Pathogenic according to our data. Variant chr5-78780398-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559729.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.1601A>G	p.Ter534Trpext*?	stop_lost	8/8	ENST00000264914.10	NP_000037.2
ARSB	XM_011543390.2	c.1601A>G	p.Ter534Trpext*?	stop_lost	9/9		XP_011541692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.1601A>G	p.Ter534Trpext*?	stop_lost	8/8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000521011.1	n.566A>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727208

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 05, 2022	For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the ARSB protein. Other variant(s) that result in a similarly extended protein product (p.*534Serext*50 and p.*534Glnext*50) have been determined to be pathogenic (PMID: 8144552; Invitae). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 559729). This variant is also known as p.*534W. This variant has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 26909334, 30524696). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the ARSB gene (p.*534Trpext*50). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last amino acid(s) of the ARSB protein and extend the protein by 50 additional amino acid residues -
Uncertain significance, flagged submission	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	Absent from GnomAD (PM2); Protein length changes as a result of a stop-loss variant (PM4) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 23, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Benign	0.88
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.084
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1554069655; hg19: chr5-78076221;