rs1554086435

Variant names:

• chr5-78955483-G-T
• rs1554086435
• NM_000046.5:c.710C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000046.5(ARSB):​c.710C>A​(p.Ala237Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:1
• Conservation: PhyloP100: 9.52

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.710C>A	p.Ala237Asp	missense_variant	Exon 4 of 8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.710C>A	p.Ala237Asp	missense_variant	Exon 4 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.710C>A	p.Ala237Asp	missense_variant	Exon 5 of 8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.710C>A	p.Ala237Asp	missense_variant	Exon 4 of 5	1		ENSP00000456339.2
ARSB	ENST00000521800.2	n.-109C>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:1 Benign:1

Dec 27, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ARSB c.710C>A (p.Ala237Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251326 control chromosomes (gnomAD). c.710C>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome; e.g. Brands_2013, Uttarilli_2017). These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Brands_2013, Uttarilli_2017). The following publications have been ascertained in the context of this evaluation (PMID: 23557332, 27826022). ClinVar contains an entry for this variant (Variation ID: 559805). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 01, 2018

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Absent from GnomAD (PM2); Multiple lines of computational evidence support a deleterious effect on the gene product (PP3) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;H;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.99
MutPred		0.63		Gain of catalytic residue at A237 (P = 0.0634);Gain of catalytic residue at A237 (P = 0.0634);Gain of catalytic residue at A237 (P = 0.0634);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1554086435; hg19: chr5-78251306;