chr5-78885599-A-T

Variant names:

• chr5-78885599-A-T
• rs1554079268
• NM_000046.5:c.1127T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_000046.5(ARSB):​c.1127T>A​(p.Val376Glu) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V376M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.27
• 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.

• 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, 0.951
• PP5: Variant 5-78885599-A-T is Pathogenic according to our data. Variant chr5-78885599-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 559675.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78885599-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 559675.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78885599-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 559675.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78885599-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 559675.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78885599-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 559675.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78885599-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 559675.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1127T>A	p.Val376Glu	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.1127T>A	p.Val376Glu	missense_variant	Exon 5 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.1127T>A	p.Val376Glu	missense_variant	Exon 6 of 8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.1127T>A	p.Val376Glu	missense_variant	Exon 5 of 5	1		ENSP00000456339.2
ARSB	ENST00000521800.2	n.309T>A		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jan 01, 2018

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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); Multiple lines of computational evidence support a deleterious effect on the gene product (PP3) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.6	H;H;.
PhyloP100		9.3
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.039	D;T;T
Polyphen		0.59	P;.;.
Vest4		0.95
MVP		1.0
MPC		0.94
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.95
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs1554079268; hg19: chr5-78181422;