chr5-78955524-A-G

Variant names:

• chr5-78955524-A-G
• rs6870443
• NM_000046.5:c.691-22T>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.691-22T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,596,616 control chromosomes in the GnomAD database, including 25,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1757 hom., cov: 33)
  • Exomes 𝑓: 0.18 (23926 hom.)
• Consequence: ARSB NM_000046.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.381
• Publications: 6 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 5-78955524-A-G is Benign according to our data. Variant chr5-78955524-A-G is described in ClinVar as Benign. ClinVar VariationId is 254740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.691-22T>C		intron_variant	Intron 3 of 7	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.691-22T>C		intron_variant	Intron 3 of 7	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.691-22T>C		intron_variant	Intron 4 of 7	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.691-22T>C		intron_variant	Intron 3 of 4	1		ENSP00000456339.2
ARSB	ENST00000521800.2	n.-150T>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21618 AN: 152104 Hom.: 1754 Cov.: 33

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.0773

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.157

GnomAD2 exomes AF: 0.168 AC: 41994 AN: 250604 AF XY: 0.175

Gnomad AFR exome AF: 0.0703

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.0807

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.178 AC: 256610 AN: 1444394 Hom.: 23926 Cov.: 28 AF XY: 0.180 AC XY: 129611 AN XY: 719760

African (AFR) AF: 0.0682 AC: 2254 AN: 33036

American (AMR) AF: 0.146 AC: 6545 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 7062 AN: 26038

East Asian (EAS) AF: 0.0624 AC: 2472 AN: 39588

South Asian (SAS) AF: 0.225 AC: 19331 AN: 85840

European-Finnish (FIN) AF: 0.116 AC: 6215 AN: 53378

Middle Eastern (MID) AF: 0.233 AC: 1257 AN: 5406

European-Non Finnish (NFE) AF: 0.183 AC: 201171 AN: 1096714

Other (OTH) AF: 0.173 AC: 10303 AN: 59714

GnomAD4 genome AF: 0.142 AC: 21622 AN: 152222 Hom.: 1757 Cov.: 33 AF XY: 0.139 AC XY: 10352 AN XY: 74434

African (AFR) AF: 0.0734 AC: 3050 AN: 41536

American (AMR) AF: 0.142 AC: 2171 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 935 AN: 3470

East Asian (EAS) AF: 0.0779 AC: 404 AN: 5188

South Asian (SAS) AF: 0.211 AC: 1019 AN: 4818

European-Finnish (FIN) AF: 0.108 AC: 1149 AN: 10610

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12382 AN: 67994

Other (OTH) AF: 0.155 AC: 328 AN: 2112

Alfa AF: 0.179 Hom.: 1160

Bravo AF: 0.141

Asia WGS AF: 0.131 AC: 454 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucopolysaccharidosis type 6 Benign:2

Jan 01, 2018

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Allele frequency greater than 5% in ExAC (BA1)

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.2
DANN	Benign	0.75
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6870443; hg19: chr5-78251347; COSMIC: COSV53730949; COSMIC: COSV53730949;