rs1339096448

Variant names:

• chr5-78984971-G-A
• rs1339096448
• NM_000046.5:c.278C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-78984971-G-A
• chr5-78984971-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000046.5(ARSB):​c.278C>T​(p.Pro93Leu) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P93S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.46
• Publications: 1 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 9 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.278C>T	p.Pro93Leu	missense_variant	Exon 1 of 8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.278C>T	p.Pro93Leu	missense_variant	Exon 1 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.278C>T	p.Pro93Leu	missense_variant	Exon 2 of 8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.278C>T	p.Pro93Leu	missense_variant	Exon 1 of 5	1		ENSP00000456339.2
ARSB	ENST00000521117.1	c.*141C>T		downstream_gene_variant		3		ENSP00000428611.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1354748 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 672328

African (AFR) AF: 0.00 AC: 0 AN: 28306

American (AMR) AF: 0.00 AC: 0 AN: 33178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23492

East Asian (EAS) AF: 0.00 AC: 0 AN: 31116

South Asian (SAS) AF: 0.00 AC: 0 AN: 73246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1060970

Other (OTH) AF: 0.00 AC: 0 AN: 55116

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 6 Uncertain:1

Jan 01, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Absent from GnomAD (PM2) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;H;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-9.1	D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.91
MutPred		0.94		Loss of glycosylation at P93 (P = 0.0398);Loss of glycosylation at P93 (P = 0.0398);Loss of glycosylation at P93 (P = 0.0398);
MVP		0.99
MPC		0.88
ClinPred		1.0	D
GERP RS		3.5
PromoterAI		-0.052	Neutral
Varity_R		0.97
gMVP		0.98
Mutation Taster		=0/100	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: rs1339096448; hg19: chr5-78280794;