rs1028653411

Positions:

• chr5-78985128-CCCCGGCGCCCGAG-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.108_120del​(p.Ser37ProfsTer15) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSB NM_000046.5 frameshift
• Clinical Significance: Pathogenic/Likely 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]

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 5-78985128-CCCCGGCGCCCGAG-C is Pathogenic according to our data. Variant chr5-78985128-CCCCGGCGCCCGAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559673.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.108_120del	p.Ser37ProfsTer15	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.108_120del	p.Ser37ProfsTer15	frameshift_variant	1/8	1	NM_000046.5	ENSP00000264914	P1
ARSB	ENST00000396151.7	c.108_120del	p.Ser37ProfsTer15	frameshift_variant	2/8	1		ENSP00000379455
ARSB	ENST00000565165.2	c.108_120del	p.Ser37ProfsTer15	frameshift_variant	1/5	1		ENSP00000456339
ARSB	ENST00000521117.1	c.108_120del	p.Ser37ProfsTer?	frameshift_variant	2/2	3		ENSP00000428611

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

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely 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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 22, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 559673). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17458871). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser37Profs*15) 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). -
Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	Frameshift variant(PVS1); Absent from GnomAD (PM2) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2022	- -

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: rs1028653411; hg19: chr5-78280951;