chr5-78885654-C-T

Position:

chr5-78885654-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:11

Conservation

PhyloP100: 4.93

Variant links:

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 links:

ARSB (HGNC:):

ARSB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.1072G>A	p.Val358Met	missense_variant	5/8	ENST00000264914.10	NP_000037.2	P15848-1A0A024RAJ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ARSB	ENST00000264914.10 linkuse as main transcript	c.1072G>A	p.Val358Met	missense_variant	5/8	1	NM_000046.5	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7 linkuse as main transcript	c.1072G>A	p.Val358Met	missense_variant	6/8	1		ENSP00000379455.3	P15848-2
ARSB	ENST00000565165.2 linkuse as main transcript	c.1072G>A	p.Val358Met	missense_variant	5/5	1		ENSP00000456339.2	A0A2U3U034
ARSB	ENST00000521800.2 linkuse as main transcript	n.254G>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

52361

AN:

151812

Hom.:

10965

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.415

AC XY:

301543

AN XY:

727226

show subpopulations

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.:

AF XY:

0.354

AC XY:

26249

AN XY:

74248

show subpopulations

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:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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:1Benign: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

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;D

MetaRNN

Benign

0.00029

T;T;T

MetaSVM

Benign

-1.5

MutationAssessor

Benign

0.67

N;N;.

PrimateAI

Benign

0.45

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over