rs1554088019

Variant names:

• chr5-78969041-C-A
• rs1554088019
• NM_000046.5:c.464G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-78969041-C-A
• chr5-78969041-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000046.5(ARSB):​c.464G>T​(p.Cys155Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C155Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.04
• Publications: 0 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 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.464G>T	p.Cys155Phe	missense_variant	Exon 2 of 8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.464G>T	p.Cys155Phe	missense_variant	Exon 2 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.464G>T	p.Cys155Phe	missense_variant	Exon 3 of 8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.464G>T	p.Cys155Phe	missense_variant	Exon 2 of 5	1		ENSP00000456339.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	-0.020	N;N;.
PhyloP100		6.0
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.038	D;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.95	P;.;.
Vest4		0.92
MutPred		0.58		Loss of ubiquitination at K153 (P = 0.0604);Loss of ubiquitination at K153 (P = 0.0604);Loss of ubiquitination at K153 (P = 0.0604);
MVP		1.0
MPC		0.96
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.93
gMVP		0.94
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554088019; hg19: chr5-78264864;