NM_000046.5:c.307_312+147del

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 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. Variant has been reported in ClinVar as Pathogenic (★).

• 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

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T is Pathogenic according to our data. Variant chr5-78984789-TGGGGCGAGAAGCCGCCGGGACCCATAACTGGGTCGGCGGTCCGAGCCCCGCCTGCCAGCGCCCGCGGCCTCAAGGGCCGGGTAGGAGCGGCAGGGCGCCGGCGAAAGGCGGGGCGGGGGCGGCGCGGGCGGCGGGGGCGCCGCGTACCTGGTA-T is described in ClinVar 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
ARSB	ENST00000396151.7	c.307_312+147del	p.Tyr103_Gln104del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 2 of 8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.307_312+147del	p.Tyr103_Gln104del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 1 of 5	1		ENSP00000456339.2
ARSB	ENST00000521117.1	c.*170_*322del		downstream_gene_variant		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: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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554089838; hg19: chr5-78280612;