rs749989641

Variant names:

• chr5-78885789-G-A
• rs749989641
• NM_000046.5:c.937C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-78885789-G-A
• chr5-78885789-G-C
• chr5-78885789-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000046.5(ARSB):​c.937C>T​(p.Pro313Ser) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P313A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.94
• Publications: 9 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 12 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000046.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-78885789-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 559826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.97
• PP5: Variant 5-78885789-G-A is Pathogenic according to our data. Variant chr5-78885789-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 559827.

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.937C>T	p.Pro313Ser	missense	Exon 5 of 8	NP_000037.2
	ARSB	NM_198709.3		c.937C>T	p.Pro313Ser	missense	Exon 6 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.937C>T	p.Pro313Ser	missense	Exon 5 of 8	ENSP00000264914.4	P15848-1
	ARSB	ENST00000396151.7	TSL:1	c.937C>T	p.Pro313Ser	missense	Exon 6 of 8	ENSP00000379455.3	P15848-2
	ARSB	ENST00000565165.2	TSL:1	c.937C>T	p.Pro313Ser	missense	Exon 5 of 5	ENSP00000456339.2	A0A2U3U034

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Mucopolysaccharidosis type 6 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.83		Gain of MoRF binding (P = 0.0452)
MVP		0.99
MPC		0.87
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.72
gMVP		0.95
Mutation Taster		=4/96	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: rs749989641; hg19: chr5-78181612;