5-78984965-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000046.5(ARSB):c.284G>A(p.Arg95Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000537 in 1,488,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000052 ( 0 hom. )
Consequence
ARSB
NM_000046.5 missense
NM_000046.5 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 5.73
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 5-78984965-C-T is Pathogenic according to our data. Variant chr5-78984965-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78984965-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.284G>A | p.Arg95Gln | missense_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.284G>A | p.Arg95Gln | missense_variant | 1/8 | 1 | NM_000046.5 | ENSP00000264914.4 | ||
ARSB | ENST00000396151.7 | c.284G>A | p.Arg95Gln | missense_variant | 2/8 | 1 | ENSP00000379455.3 | |||
ARSB | ENST00000565165.2 | c.284G>A | p.Arg95Gln | missense_variant | 1/5 | 1 | ENSP00000456339.2 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151696Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
1
AN:
151696
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000678 AC: 1AN: 147456Hom.: 0 AF XY: 0.0000119 AC XY: 1AN XY: 84196
GnomAD3 exomes
AF:
AC:
1
AN:
147456
Hom.:
AF XY:
AC XY:
1
AN XY:
84196
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000524 AC: 7AN: 1336738Hom.: 0 Cov.: 31 AF XY: 0.00000755 AC XY: 5AN XY: 662560
GnomAD4 exome
AF:
AC:
7
AN:
1336738
Hom.:
Cov.:
31
AF XY:
AC XY:
5
AN XY:
662560
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151696Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74062
GnomAD4 genome
AF:
AC:
1
AN:
151696
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
74062
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 95 of the ARSB protein (p.Arg95Gln). This variant is present in population databases (rs118203942, gnomAD 0.001%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 8651289; Invitae). ClinVar contains an entry for this variant (Variation ID: 884). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSB protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSB function (PMID: 8651289). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | curation | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2018 | In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAc (PM2); Reputable source identifies as pathogenic (PP5) - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1996 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 25, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Loss of methylation at R95 (P = 0.0491);Loss of methylation at R95 (P = 0.0491);Loss of methylation at R95 (P = 0.0491);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at