rs431905495

Variant names:

Variant summary

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

The NM_000046.5(ARSB):c.1143-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000248 in 1,612,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ARSB
NM_000046.5 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.92

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 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.4, offset of 5, new splice context is: aaaattgttttccactgaAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-78839427-C-G is Pathogenic according to our data. Variant chr5-78839427-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78839427-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5 link	c.1143-1G>C		splice_acceptor_variant, intron_variant	Intron 5 of 7	ENST00000264914.10	NP_000037.2	P15848-1A0A024RAJ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10 link	c.1143-1G>C		splice_acceptor_variant, intron_variant	Intron 5 of 7	1	NM_000046.5	ENSP00000264914.4		P15848-1
ARSB	ENST00000396151.7 link	c.1143-1G>C		splice_acceptor_variant, intron_variant	Intron 6 of 7	1		ENSP00000379455.3		P15848-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460864

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6

Pathogenic:8

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ARSB c.1143-1G>C variant occurs in a canonical splice site (acceptor) and is predicted to disrupt or distort the normal gene product. The c.1143-1G>C variant has been reported in four studies in which it is found in at least 14 individuals with mucopolysaccharidosis, type VI, including one who carried the variant in a homozygous state and 13, including two siblings, who carried the variant in a compound heterozygous state (Garrido et al. 2007; Karageorgos et al. 2007; Garrido et al. 2008; Giraldo et al. 2016). The clinical phenotypes of these patients ranged from intermediate to severe. The c.1143-1G>C variant was absent from 50 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Functional studies showed that the variant resulted in lower levels of protein compared to wildtype, a range of 1-23% enzyme activity compared to controls, was subject to nonsense-mediated decay, and did not fully correctly localize to the lysosome (Karageorgos et al. 2007; Garrido et al. 2008). Based on the potential impact of splice acceptor variants and the evidence from the literature, the c.1143-1G>C variant is classified as pathogenic for mucopolysaccharidosis, type VI. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Feb 11, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ARSB c.1143-1G>C variant substitutes a highly conserved nucleotide at the canonical splice acceptor site in intron 5. 4/5 splice prediction tools predict abrogation of the splice acceptor site. The prediction results are verified by a functional assay: RT-PCR on a patients fibroblasts showed skipping of exon 6 (Garrido_2007). Exon 6 is encodes a part of alkaline-phosphatase-like, core domain (InterPro), thus skipping of exon 6 is expected to form non-functional protein. This variant is absent in 121248 control chromosomes from the broad and large populations of ExAC. It is found in several patients with mucopolysaccharidosis type VI with consistent recessive genotypes including evidence of cosegregation with disease (Karageorgos_2007, Garrido_2007, and Garrido_2015). In addition, multiple clinical reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -

Sep 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in exon 6 skipping and introduces a premature termination codon (PMID: 18406185). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 887). Disruption of this splice site has been observed in individuals with mucopolysaccharidosis VI (PMID: 17458871). This variant is present in population databases (rs431905495, gnomAD 0.1%). This sequence change affects an acceptor splice site in intron 5 of the ARSB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -

Jan 01, 2018

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Splicing variant in canonical site (PVS1); In vitro functional studies supportive of a damaging effect on the gene product (demonstrated nonsense mediated RNA decay; PS3); Very low frequency in GnomAD (PM2); Reputable source identifies as pathogenic (PP5) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.68

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.89

GERP RS

5.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.89

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.89

Position offset: -1

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