rs118203941

chr5-78781974-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_000046.5(ARSB):c.1214G>A(p.Cys405Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000279 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

ARSB
NM_000046.5 missense, splice_region

Scores

Splicing: ADA: 0.06609

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 3.93

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]

ARSB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a disulfide_bond (size 42) in uniprot entity ARSB_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000046.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

PP5

Variant 5-78781974-C-T is Pathogenic according to our data. Variant chr5-78781974-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ARSB	NM_000046.5 linkuse as main transcript	c.1214G>A	p.Cys405Tyr	missense_variant, splice_region_variant	7/8	ENST00000264914.10
ARSB	XM_011543390.2 linkuse as main transcript	c.1214G>A	p.Cys405Tyr	missense_variant, splice_region_variant	8/9
ARSB	XR_001742066.3 linkuse as main transcript	n.1457G>A		splice_region_variant, non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSB	ENST00000264914.10 linkuse as main transcript	c.1214G>A	p.Cys405Tyr	missense_variant, splice_region_variant	7/8	1	NM_000046.5	P1	P15848-1
ARSB	ENST00000521011.1 linkuse as main transcript	n.179G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251408

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135872

show subpopulations

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727200

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

show subpopulations

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:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000779

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 03, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	Absent from GnomAD (PM2) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 405 of the ARSB protein (p.Cys405Tyr). This variant is present in population databases (rs118203941, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type VI (PMID: 1550123, 17458871; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 880). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 14, 2022	- -

Mucopolysaccharidosis, type vi, severe

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1992

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 12, 2015

- -

Metachromatic leukodystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 24, 2018

Variant summary: ARSB c.1214G>A (p.Cys405Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Though the variant is located at an exon-intron junction, 5/5 computational tools predict no significant impact on normal splicing. These predictions have been confirmed by functional studies, where full-length mRNA containing the mutation c.1214G>A was detected (Jin 1992, Karageorgos 2007), predicted to result in a protein with the missense change p.C405Y. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246184 control chromosomes. This frequency is lower than expected for a pathogenic variant in ARSB causing Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (2e-05 vs 0.0022), allowing no conclusion about variant significance. The variant, c.1214G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) presenting with a slowly progressing, milder disease phenotype (Jin 1992, Karageorgos 2007). These data indicate that the variant is likely to be associated with disease. These publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Jin 1992, Karageorgos 2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.19

Cadd

Uncertain

Dann

Benign

0.52

DEOGEN2

Uncertain

0.62

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.00016

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.57

Sift

Benign

0.13

Sift4G

Benign

0.66

Polyphen

0.0010

Vest4

0.82

MVP

0.98

MPC

0.41

ClinPred

0.60

GERP RS

5.8

Varity_R

0.21

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.066

dbscSNV1_RF

Benign

0.44

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over