NM_000046.5:c.1028A>T

Variant names:

• chr5-78885698-T-A
• rs1554079305
• NM_000046.5:c.1028A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000046.5(ARSB):​c.1028A>T​(p.Lys343Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05
• 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 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1028A>T	p.Lys343Met	missense_variant	Exon 5 of 8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.1028A>T	p.Lys343Met	missense_variant	Exon 5 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.1028A>T	p.Lys343Met	missense_variant	Exon 6 of 8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.1028A>T	p.Lys343Met	missense_variant	Exon 5 of 5	1		ENSP00000456339.2
ARSB	ENST00000521800.2	n.210A>T		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

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	Benign	0.16
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;.
Eigen	Benign	-0.095
Eigen_PC	Benign	-0.051
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.63	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.6	L;L;.
PhyloP100		2.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.046	D;D;D
Sift4G	Benign	0.081	T;T;T
Polyphen		0.24	B;.;.
Vest4		0.67
MutPred		0.85		Loss of ubiquitination at K343 (P = 0.0381);Loss of ubiquitination at K343 (P = 0.0381);Loss of ubiquitination at K343 (P = 0.0381);
MVP		0.98
MPC		0.55
ClinPred		0.39	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.76
Mutation Taster		=17/83	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: rs1554079305; hg19: chr5-78181521;