chr5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T

Variant names:

• chr5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T
• rs1554089838
• NM_000046.5:c.307_312+147del

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000046.5(ARSB):​c.307_312+147del​(p.Tyr103_Gln104del) variant causes a splice donor, conservative inframe deletion, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y103Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSB NM_000046.5 splice_donor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0190
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Illumina, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ENSG00000308325 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PP5: Variant 5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T is Pathogenic according to our data. Variant chr5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T is described in CliVar as Pathogenic. Clinvar id is 559767.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T is described in CliVar as Pathogenic. Clinvar id is 559767.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T is described in CliVar as Pathogenic. Clinvar id is 559767.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T is described in CliVar as Pathogenic. Clinvar id is 559767.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T is described in CliVar as Pathogenic. Clinvar id is 559767.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T is described in CliVar as Pathogenic. Clinvar id is 559767.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.307_312+147del	p.Tyr103_Gln104del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 1 of 8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.307_312+147del	p.Tyr103_Gln104del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 1 of 8	1	NM_000046.5	ENSP00000264914.4

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:1

Jan 01, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.019
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554089838; hg19: chr5-78280612;