chr5-78964597-A-C

Variant names:

• chr5-78964597-A-C
• rs1484763838
• NM_000046.5:c.509T>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000046.5(ARSB):​c.509T>G​(p.Leu170Arg) 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 (★). ClinVar reports functional evidence for this variant: "SCV000803088: "In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L170L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.94
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Illumina, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000803088: "In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3);"
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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, 0.959
• PP5: Variant 5-78964597-A-C is Pathogenic according to our data. Variant chr5-78964597-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 559793.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000046.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	NM_000046.5	MANE Select	c.509T>G	p.Leu170Arg	missense	Exon 3 of 8	NP_000037.2
	ARSB	NM_198709.3		c.509T>G	p.Leu170Arg	missense	Exon 4 of 8	NP_942002.1	P15848-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	ENST00000264914.10	TSL:1 MANE Select	c.509T>G	p.Leu170Arg	missense	Exon 3 of 8	ENSP00000264914.4	P15848-1
	ARSB	ENST00000396151.7	TSL:1	c.509T>G	p.Leu170Arg	missense	Exon 4 of 8	ENSP00000379455.3	P15848-2
	ARSB	ENST00000565165.2	TSL:1	c.509T>G	p.Leu170Arg	missense	Exon 3 of 5	ENSP00000456339.2	A0A2U3U034

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mucopolysaccharidosis type 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	0.65	N
PhyloP100		3.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.77
Sift	Benign	0.21	T
Sift4G	Benign	0.67	T
Polyphen		0.96	D
Vest4		0.92
MutPred		0.87		Gain of disorder (P = 0.0278)
MVP		1.0
MPC		0.98
ClinPred		0.87	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.88
Mutation Taster		=5/95	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: rs1484763838; hg19: chr5-78260420;