rs1554032099

Positions:

• chr5-78984968-G-A
• chr5-78984968-G-C
• chr5-78984968-G-T

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.281C>T​(p.Ser94Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000298 in 1,341,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.63

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, 0.99
• PP5: Variant 5-78984968-G-A is Pathogenic according to our data. Variant chr5-78984968-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445287.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.281C>T	p.Ser94Leu	missense_variant	1/8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.281C>T	p.Ser94Leu	missense_variant	1/8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.281C>T	p.Ser94Leu	missense_variant	2/8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.281C>T	p.Ser94Leu	missense_variant	1/5	1		ENSP00000456339.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000298 AC: 4 AN: 1341736 Hom.: 0 Cov.: 31 AF XY: 0.00000451 AC XY: 3 AN XY: 665432

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000380

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Pathogenic, criteria provided, single submitter

research

Medical Molecular Genetics Department, National Research Center

Dec 01, 2015

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 16, 2024

Variant summary: ARSB c.281C>T (p.Ser94Leu) results in a non-conservative amino acid change located in the Sulfatase, N-terminal (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.281C>T in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 445287). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.83
MutPred		0.93		Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);
MVP		0.99
MPC		0.80
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.99
gMVP		0.99

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: rs1554032099; hg19: chr5-78280791;