rs1554086435

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Illumina, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000046.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 85 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 0.63089 (below the threshold of 3.09). Trascript score misZ: -0.06109 (below the threshold of 3.09). GenCC associations: The gene is linked to mucopolysaccharidosis type 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000046.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	NM_000046.5	MANE Select	c.710C>A	p.Ala237Asp	missense	Exon 4 of 8	NP_000037.2
	ARSB	NM_198709.3		c.710C>A	p.Ala237Asp	missense	Exon 5 of 8	NP_942002.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	ENST00000264914.10	TSL:1 MANE Select	c.710C>A	p.Ala237Asp	missense	Exon 4 of 8	ENSP00000264914.4
	ARSB	ENST00000396151.7	TSL:1	c.710C>A	p.Ala237Asp	missense	Exon 5 of 8	ENSP00000379455.3
	ARSB	ENST00000565165.2	TSL:1	c.710C>A	p.Ala237Asp	missense	Exon 4 of 5	ENSP00000456339.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	1	Mucopolysaccharidosis type 6 (2)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.63		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
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs1554086435; hg19: chr5-78251306;