rs72762973

Positions:

• chr5-78885754-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000264914.10(ARSB):​c.972A>G​(p.Gly324=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0639 in 1,613,994 control chromosomes in the GnomAD database, including 3,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (312 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3534 hom.)
• Consequence: ARSB ENST00000264914.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.285

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-78885754-T-C is Benign according to our data. Variant chr5-78885754-T-C is described in ClinVar as [Benign]. Clinvar id is 92357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.285 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.972A>G	p.Gly324=	synonymous_variant	5/8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.972A>G	p.Gly324=	synonymous_variant	5/8	1	NM_000046.5	ENSP00000264914	P1
ARSB	ENST00000396151.7	c.972A>G	p.Gly324=	synonymous_variant	6/8	1		ENSP00000379455
ARSB	ENST00000565165.2	c.972A>G	p.Gly324=	synonymous_variant	5/5	1		ENSP00000456339
ARSB	ENST00000521800.2	n.154A>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8103 AN: 151984 Hom.: 312 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0463

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0739

Gnomad OTH AF: 0.0489

GnomAD3 exomes AF: 0.0529 AC: 13290 AN: 251348 Hom.: 472 AF XY: 0.0521 AC XY: 7073 AN XY: 135842

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.0314

Gnomad ASJ exome AF: 0.0514

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0145

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0725

Gnomad OTH exome AF: 0.0590

GnomAD4 exome AF: 0.0650 AC: 95022 AN: 1461892 Hom.: 3534 Cov.: 35 AF XY: 0.0637 AC XY: 46297 AN XY: 727246

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.0340

Gnomad4 ASJ exome AF: 0.0522

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.0730

Gnomad4 OTH exome AF: 0.0578

GnomAD4 genome AF: 0.0533 AC: 8100 AN: 152102 Hom.: 312 Cov.: 32 AF XY: 0.0537 AC XY: 3995 AN XY: 74334

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.0462

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.0739

Gnomad4 OTH AF: 0.0484

Alfa AF: 0.0619 Hom.: 169

Bravo AF: 0.0459

Asia WGS AF: 0.00693 AC: 26 AN: 3478

EpiCase AF: 0.0706

EpiControl AF: 0.0664

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.8
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs72762973; hg19: chr5-78181577; COSMIC: COSV53729712;