rs1065757

Positions:

• chr5-78885654-C-A
• chr5-78885654-C-G
• chr5-78885654-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000046.5(ARSB):​c.1072G>T​(p.Val358Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V358M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1072G>T	p.Val358Leu	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.1072G>T	p.Val358Leu	missense_variant	5/8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.1072G>T	p.Val358Leu	missense_variant	6/8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.1072G>T	p.Val358Leu	missense_variant	5/5	1		ENSP00000456339.2
ARSB	ENST00000521800.2	n.254G>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461866 Hom.: 0 Cov.: 71 AF XY: 0.00 AC XY: 0 AN XY: 727232

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 09, 2024

Variant summary: ARSB c.1072G>T (p.Val358Leu) results in a conservative amino acid change located in the Sulfatase, N-terminal (IPR047115) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251208 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1072G>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome). Co-occurrences with other pathogenic variant(s) have been reported (ARSB c.979G>T , p.Arg327X, Fang_2022), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 34813777). No submitters have cited clinical-significance assessments for this variant to ClinVar. 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	Benign	0.20
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.
Eigen	Benign	-0.048
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	-0.94	N;N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.36	B;.;.
Vest4		0.16
MutPred		0.20		Loss of methylation at R362 (P = 0.1446);Loss of methylation at R362 (P = 0.1446);Loss of methylation at R362 (P = 0.1446);
MVP		0.91
MPC		0.30
ClinPred		0.87	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.85

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: rs1065757; hg19: chr5-78181477;