NM_000046.5:c.500-1528T>C

Variant names:

• chr5-78966134-A-G
• rs921945
• NM_000046.5:c.500-1528T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000046.5(ARSB):​c.500-1528T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 152,124 control chromosomes in the GnomAD database, including 6,641 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (6641 hom., cov: 33)
• Consequence: ARSB NM_000046.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.536
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.500-1528T>C		intron_variant	Intron 2 of 7	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.500-1528T>C		intron_variant	Intron 2 of 7	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.500-1528T>C		intron_variant	Intron 3 of 7	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.500-1528T>C		intron_variant	Intron 2 of 4	1		ENSP00000456339.2

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40210 AN: 152006 Hom.: 6609 Cov.: 33

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.265 AC: 40289 AN: 152124 Hom.: 6641 Cov.: 33 AF XY: 0.260 AC XY: 19328 AN XY: 74386

African (AFR) AF: 0.469 AC: 19449 AN: 41460

American (AMR) AF: 0.199 AC: 3038 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1035 AN: 3468

East Asian (EAS) AF: 0.110 AC: 571 AN: 5188

South Asian (SAS) AF: 0.298 AC: 1436 AN: 4820

European-Finnish (FIN) AF: 0.110 AC: 1161 AN: 10598

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12864 AN: 67982

Other (OTH) AF: 0.254 AC: 538 AN: 2116

Alfa AF: 0.233 Hom.: 2607

Bravo AF: 0.280

Asia WGS AF: 0.236 AC: 821 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	6.3
DANN	Benign	0.43
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism (auto)

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: rs921945; hg19: chr5-78261957;