rs3733895

Variant names:

• chr5-78969218-A-G
• rs3733895
• NM_000046.5:c.313-26T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000046.5(ARSB):​c.313-26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,611,296 control chromosomes in the GnomAD database, including 101,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7526 hom., cov: 32)
  • Exomes 𝑓: 0.35 (93571 hom.)
• Consequence: ARSB NM_000046.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.401
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-78969218-A-G is Benign according to our data. Variant chr5-78969218-A-G is described in ClinVar as Benign. ClinVar VariationId is 254739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

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.313-26T>C		intron	N/A	NP_000037.2
	ARSB	NM_198709.3		c.313-26T>C		intron	N/A	NP_942002.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	ENST00000264914.10	TSL:1 MANE Select	c.313-26T>C		intron	N/A	ENSP00000264914.4
	ARSB	ENST00000396151.7	TSL:1	c.313-26T>C		intron	N/A	ENSP00000379455.3
	ARSB	ENST00000565165.2	TSL:1	c.313-26T>C		intron	N/A	ENSP00000456339.2

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45813 AN: 151976 Hom.: 7521 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.324 AC: 80995 AN: 250196 AF XY: 0.325

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.216

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.354 AC: 516648 AN: 1459202 Hom.: 93571 Cov.: 31 AF XY: 0.353 AC XY: 256015 AN XY: 726150

African (AFR) AF: 0.154 AC: 5153 AN: 33408

American (AMR) AF: 0.301 AC: 13441 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10495 AN: 26120

East Asian (EAS) AF: 0.258 AC: 10215 AN: 39662

South Asian (SAS) AF: 0.269 AC: 23176 AN: 86174

European-Finnish (FIN) AF: 0.381 AC: 20332 AN: 53392

Middle Eastern (MID) AF: 0.335 AC: 1892 AN: 5652

European-Non Finnish (NFE) AF: 0.371 AC: 411481 AN: 1109794

Other (OTH) AF: 0.339 AC: 20463 AN: 60286

GnomAD4 genome AF: 0.301 AC: 45840 AN: 152094 Hom.: 7526 Cov.: 32 AF XY: 0.301 AC XY: 22414 AN XY: 74344

African (AFR) AF: 0.161 AC: 6678 AN: 41530

American (AMR) AF: 0.316 AC: 4823 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1395 AN: 3468

East Asian (EAS) AF: 0.227 AC: 1169 AN: 5160

South Asian (SAS) AF: 0.267 AC: 1289 AN: 4820

European-Finnish (FIN) AF: 0.386 AC: 4081 AN: 10560

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.371 AC: 25204 AN: 67958

Other (OTH) AF: 0.328 AC: 693 AN: 2110

Alfa AF: 0.343 Hom.: 31539

Bravo AF: 0.291

Asia WGS AF: 0.251 AC: 874 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucopolysaccharidosis type 6 Benign:1

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3733895; hg19: chr5-78265041; COSMIC: COSV53720346;