rs118203943

Variant names:

• chr5-78964477-T-A
• rs118203943
• NM_000046.5:c.629A>T

Your query was ambiguous. Multiple possible variants found:

• chr5-78964477-T-A
• chr5-78964477-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000046.5(ARSB):​c.629A>T​(p.Tyr210Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y210C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.51
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-78964477-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 885.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.629A>T	p.Tyr210Phe	missense_variant	Exon 3 of 8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.629A>T	p.Tyr210Phe	missense_variant	Exon 3 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.629A>T	p.Tyr210Phe	missense_variant	Exon 4 of 8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.629A>T	p.Tyr210Phe	missense_variant	Exon 3 of 5	1		ENSP00000456339.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;L;.
PhyloP100		5.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.029	D;D;D
Sift4G	Uncertain	0.032	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.57
MutPred		0.63		Loss of ubiquitination at K207 (P = 0.0578);Loss of ubiquitination at K207 (P = 0.0578);Loss of ubiquitination at K207 (P = 0.0578);
MVP		0.97
MPC		0.83
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.78
gMVP		0.87
Mutation Taster		=39/61	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: rs118203943; hg19: chr5-78260300; COSMIC: COSV53731005;