5-78885654-C-T

Position:

• chr5-78885654-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000046.5(ARSB):​c.1072G>A​(p.Val358Met) variant causes a missense change. The variant allele was found at a frequency of 0.413 in 1,613,786 control chromosomes in the GnomAD database, including 144,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V358L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.34 (10960 hom., cov: 31)
  • Exomes 𝑓: 0.42 (133445 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:11
• Conservation: PhyloP100: 4.93

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.8827786E-4).
• BP6: Variant 5-78885654-C-T is Benign according to our data. Variant chr5-78885654-C-T is described in ClinVar as [Benign]. Clinvar id is 92350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78885654-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1072G>A	p.Val358Met	missense_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.1072G>A	p.Val358Met	missense_variant	5/8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.1072G>A	p.Val358Met	missense_variant	6/8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.1072G>A	p.Val358Met	missense_variant	5/5	1		ENSP00000456339.2
ARSB	ENST00000521800.2	n.254G>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52361 AN: 151812 Hom.: 10965 Cov.: 31

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.340

GnomAD3 exomes AF: 0.399 AC: 100122 AN: 251208 Hom.: 21703 AF XY: 0.396 AC XY: 53746 AN XY: 135760

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.434

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.391

Gnomad SAS exome AF: 0.251

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.440

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.420 AC: 613553 AN: 1461856 Hom.: 133445 Cov.: 71 AF XY: 0.415 AC XY: 301543 AN XY: 727226

Gnomad4 AFR exome AF: 0.0966

Gnomad4 AMR exome AF: 0.427

Gnomad4 ASJ exome AF: 0.340

Gnomad4 EAS exome AF: 0.374

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.578

Gnomad4 NFE exome AF: 0.439

Gnomad4 OTH exome AF: 0.396

GnomAD4 genome AF: 0.345 AC: 52364 AN: 151930 Hom.: 10960 Cov.: 31 AF XY: 0.354 AC XY: 26249 AN XY: 74248

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.337

Gnomad4 EAS AF: 0.380

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.600

Gnomad4 NFE AF: 0.438

Gnomad4 OTH AF: 0.340

Alfa AF: 0.413 Hom.: 28916

Bravo AF: 0.325

TwinsUK AF: 0.421 AC: 1562

ALSPAC AF: 0.413 AC: 1591

ESP6500AA AF: 0.114 AC: 504

ESP6500EA AF: 0.432 AC: 3719

ExAC AF: 0.391 AC: 47428

Asia WGS AF: 0.264 AC: 920 AN: 3478

EpiCase AF: 0.419

EpiControl AF: 0.425

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -
Benign, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	Allele frequency > 5% in ExAC (BA1); Classified benign by a reputable source (BP6) -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2014	- -

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30335002, 27826022, 18406185) -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.00029	T;T;T
MetaSVM	Benign	-1.5	T
MutationAssessor	Benign	0.67	N;N;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.24
MPC		0.81
ClinPred		0.017	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.82

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: rs1065757; hg19: chr5-78181477; COSMIC: COSV53719568;