rs79970603

Positions:

• chr5-78885678-T-A
• chr5-78885678-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_000046.5(ARSB):​c.1048A>T​(p.Ile350Phe) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant 5-78885678-T-A is Pathogenic according to our data. Variant chr5-78885678-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559668.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1048A>T	p.Ile350Phe	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.1048A>T	p.Ile350Phe	missense_variant	5/8	1	NM_000046.5	ENSP00000264914	P1
ARSB	ENST00000396151.7	c.1048A>T	p.Ile350Phe	missense_variant	6/8	1		ENSP00000379455
ARSB	ENST00000565165.2	c.1048A>T	p.Ile350Phe	missense_variant	5/5	1		ENSP00000456339
ARSB	ENST00000521800.2	n.230A>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Jan 01, 2018

In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Absent from GnomAD (PM2) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.76
MutPred		0.59		Loss of MoRF binding (P = 0.187);Loss of MoRF binding (P = 0.187);Loss of MoRF binding (P = 0.187);
MVP		0.98
MPC		1.1
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.94

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: rs79970603; hg19: chr5-78181501;