rs1554032175

Variant names:

• chr5-78985043-G-A
• rs1554032175
• NM_000046.5:c.206C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000046.5(ARSB):​c.206C>T​(p.Thr69Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.32
• 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 10 ACMG points.

• PM1: In a hotspot region, there are 7 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, 0.982
• PP5: Variant 5-78985043-G-A is Pathogenic according to our data. Variant chr5-78985043-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 559736.

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.206C>T	p.Thr69Met	missense	Exon 1 of 8	NP_000037.2
	ARSB	NM_198709.3		c.206C>T	p.Thr69Met	missense	Exon 2 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.206C>T	p.Thr69Met	missense	Exon 1 of 8	ENSP00000264914.4	P15848-1
	ARSB	ENST00000396151.7	TSL:1	c.206C>T	p.Thr69Met	missense	Exon 2 of 8	ENSP00000379455.3	P15848-2
	ARSB	ENST00000565165.2	TSL:1	c.206C>T	p.Thr69Met	missense	Exon 1 of 5	ENSP00000456339.2	A0A2U3U034

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1390070 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 691100

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28760

American (AMR) AF: 0.0000276 AC: 1 AN: 36284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24224

East Asian (EAS) AF: 0.00 AC: 0 AN: 32238

South Asian (SAS) AF: 0.00 AC: 0 AN: 78598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5196

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078232

Other (OTH) AF: 0.00 AC: 0 AN: 56860

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.88		Loss of phosphorylation at T69 (P = 0.0253)
MVP		0.99
MPC		0.89
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		0.030	Neutral
Varity_R		0.94
gMVP		0.97
Mutation Taster		=54/46	polymorphism

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: rs1554032175; hg19: chr5-78280866;