chr5-78885582-A-T

Position:

• chr5-78885582-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000264914.10(ARSB):​c.1142+2T>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARSB ENST00000264914.10 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.06

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 (HGNC:):

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, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-78885582-A-T is Pathogenic according to our data. Variant chr5-78885582-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1142+2T>A		splice_donor_variant, intron_variant		ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000565165.2	c.1144T>A	p.Tyr382Asn	missense_variant	5/5	1		ENSP00000456339.2
ARSB	ENST00000264914.10	c.1142+2T>A		splice_donor_variant, intron_variant		1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.1142+2T>A		splice_donor_variant, intron_variant		1		ENSP00000379455.3
ARSB	ENST00000521800.2	n.324+2T>A		splice_donor_variant, intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 24, 2022	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (PMID: 17643332). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 559679). Disruption of this splice site has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17643332). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor 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. -
Likely 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); Absent from GnomAD (PM2) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781510986; hg19: chr5-78181405;