rs991104525

chr5-78969051-G-Achr5-78969051-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000046.5(ARSB):c.454C>T(p.Arg152Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,614,012 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R152Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.81

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 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000046.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-78969050-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 800876.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant 5-78969051-G-A is Pathogenic according to our data. Variant chr5-78969051-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 496789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78969051-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSB	NM_000046.5	c.454C>T	p.Arg152Trp	missense_variant	2/8	ENST00000264914.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSB	ENST00000264914.10	c.454C>T	p.Arg152Trp	missense_variant	2/8	1	NM_000046.5	P1
ARSB	ENST00000396151.7	c.454C>T	p.Arg152Trp	missense_variant	3/8	1
ARSB	ENST00000565165.2	c.454C>T	p.Arg152Trp	missense_variant	2/5	1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251474 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 60 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 22, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 152 of the ARSB protein (p.Arg152Trp). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individuals with mucopolysaccharidosis type VI (PMID: 8125475, 17458871, 23557332, 24221504). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 496789). 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: 23557332). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 02, 2022	- -
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); Prevalence of variant in affected is significantly increased compared to controls (PS4); Very low frequence in GnomAd (PM2);Reputable source identifies as pathogenic (PP5) -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2022	Variant summary: ARSB c.454C>T (p.Arg152Trp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes. c.454C>T has been reported in the literature as a biallelic homozygous/compound heterozygous genotype in multiple individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (example, Voskoboeva_1994, Karageorgos_2007, Jurecka_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Karageorgos_2007). The most pronounced variant effect results in <10% of normal activity in fibroblasts from an individual with a homozygous genotype. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2023	Published functional studies demonstrate significantly decreased ARSB activity compared to wild type and no expression of the mature ARSB enzyme (Brands et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8125475, 31009684, 22441840, 28552677, 23557332, 22133300, 10923267, 17458871, 24875751, 23633437, 30118150, 35118118, 35052464, 33209960, 21917494, 24221504) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Pathogenic	0.83
Sift	Benign	0.041	D;D;D
Sift4G	Uncertain	0.047	D;D;D
Polyphen		0.27	B;.;.
Vest4		0.47
MVP		0.99
MPC		0.80
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.58
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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

Other links and lift over

dbSNP: rs991104525; hg19: chr5-78264874; COSMIC: COSV53730185;