rs431905495

Variant names:

• chr5-78839427-C-G
• rs431905495
• NM_000046.5:c.1143-1G>C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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

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 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	c.1143-1G>C		splice_acceptor_variant, intron_variant	Intron 5 of 7	ENST00000264914.10	NP_000037.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152084 Hom.: 0 Cov.: 32

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: 1 AN: 1460864 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726766

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: 3 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74288

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

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2016	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 08, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 15, 2023	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. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	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	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.89	D
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

Other links and lift over

dbSNP: rs431905495; hg19: chr5-78135250;