chr5-78984978-A-C

Variant names:

• chr5-78984978-A-C
• rs1554032113
• NM_000046.5:c.271T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000046.5(ARSB):​c.271T>G​(p.Cys91Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000733 in 1,364,156 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C91Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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, 0.987

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	NM_000046.5	MANE Select	c.271T>G	p.Cys91Gly	missense	Exon 1 of 8	NP_000037.2
	ARSB	NM_198709.3		c.271T>G	p.Cys91Gly	missense	Exon 2 of 8	NP_942002.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	ENST00000264914.10	TSL:1 MANE Select	c.271T>G	p.Cys91Gly	missense	Exon 1 of 8	ENSP00000264914.4
	ARSB	ENST00000396151.7	TSL:1	c.271T>G	p.Cys91Gly	missense	Exon 2 of 8	ENSP00000379455.3
	ARSB	ENST00000565165.2	TSL:1	c.271T>G	p.Cys91Gly	missense	Exon 1 of 5	ENSP00000456339.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1364156 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 677412

African (AFR) AF: 0.00 AC: 0 AN: 28452

American (AMR) AF: 0.00 AC: 0 AN: 33878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23694

East Asian (EAS) AF: 0.00 AC: 0 AN: 31456

South Asian (SAS) AF: 0.00 AC: 0 AN: 74668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4414

European-Non Finnish (NFE) AF: 9.38e-7 AC: 1 AN: 1065884

Other (OTH) AF: 0.00 AC: 0 AN: 55536

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 6 Uncertain:1

Mar 24, 2025

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	32
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.93		Gain of disorder (P = 0.0051)
MVP		1.0
MPC		0.61
ClinPred		1.0	D
GERP RS		3.4
PromoterAI		0.015	Neutral
Varity_R		0.97
gMVP		0.99
Mutation Taster		=2/98	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: rs1554032113; hg19: chr5-78280801;