5-78955428-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000046.5(ARSB):​c.765T>A​(p.Tyr255*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.206
Variant links:
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]

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ACMG classification

Classification made for transcript

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 5-78955428-A-T is Pathogenic according to our data. Variant chr5-78955428-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARSBNM_000046.5 linkc.765T>A p.Tyr255* stop_gained Exon 4 of 8 ENST00000264914.10 NP_000037.2 P15848-1A0A024RAJ9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARSBENST00000264914.10 linkc.765T>A p.Tyr255* stop_gained Exon 4 of 8 1 NM_000046.5 ENSP00000264914.4 P15848-1
ARSBENST00000396151.7 linkc.765T>A p.Tyr255* stop_gained Exon 5 of 8 1 ENSP00000379455.3 P15848-2
ARSBENST00000565165.2 linkc.765T>A p.Tyr255* stop_gained Exon 4 of 5 1 ENSP00000456339.2 A0A2U3U034
ARSBENST00000521800.2 linkn.-54T>A upstream_gene_variant 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:3
Feb 14, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr255*) 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: 15603718). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 559812). For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2018
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

Nonsense variant (PVS1); Absent from GnomAD (PM2) -

Oct 17, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ARSB c.765T>A (p.Tyr255X) 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. The variant was absent in 251380 control chromosomes (gnomAD). c.765T>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome)(But_2011, Tomanin_2018, Lam_2004). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.68
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
26
DANN
Uncertain
0.99
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.23
N
Vest4
0.98
GERP RS
-7.4

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554086414; hg19: chr5-78251251; API