rs1554079311

Positions:

• chr5-78885725-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000046.5(ARSB):​c.1001G>T​(p.Ser334Ile) 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: 32)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.86

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 5-78885725-C-A is Pathogenic according to our data. Variant chr5-78885725-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 559664.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1001G>T	p.Ser334Ile	missense_variant	5/8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.1001G>T	p.Ser334Ile	missense_variant	5/8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.1001G>T	p.Ser334Ile	missense_variant	6/8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.1001G>T	p.Ser334Ile	missense_variant	5/5	1		ENSP00000456339.2
ARSB	ENST00000521800.2	n.183G>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	Absent from GnomAD (PM2); Multiple lines of computational evidence support a deleterious effect on the gene product (PP3) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.045	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.87
MutPred		0.77		Loss of catalytic residue at S334 (P = 0.0246);Loss of catalytic residue at S334 (P = 0.0246);Loss of catalytic residue at S334 (P = 0.0246);
MVP		0.99
MPC		0.95
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96

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: rs1554079311; hg19: chr5-78181548; COSMIC: COSV99365394;