rs201168448

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000046.5(ARSB):c.98C>T(p.Ala33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,453,254 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 19 hom., cov: 33)

Exomes 𝑓: 0.012 ( 130 hom. )

Consequence

ARSB
NM_000046.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.567

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=0.0036388934).

BP6

Variant 5-78985151-G-A is Benign according to our data. Variant chr5-78985151-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00982 (1488/151474) while in subpopulation AMR AF= 0.012 (183/15246). AF 95% confidence interval is 0.0111. There are 19 homozygotes in gnomad4. There are 820 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5 linkuse as main transcript	c.98C>T	p.Ala33Val	missense_variant	1/8	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.98C>T	p.Ala33Val	missense_variant	1/8	1	NM_000046.5	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7 linkuse as main transcript	c.98C>T	p.Ala33Val	missense_variant	2/8	1		ENSP00000379455.3	P15848-2
ARSB	ENST00000565165.2 linkuse as main transcript	c.98C>T	p.Ala33Val	missense_variant	1/5	1		ENSP00000456339.2	A0A2U3U034
ARSB	ENST00000521117.1 linkuse as main transcript	c.98C>T	p.Ala33Val	missense_variant	2/2	3		ENSP00000428611.1	E5RHC4

Frequencies

GnomAD3 genomes

AF:

0.00984

AC:

1489

AN:

151366

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00233

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.00981

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.0344

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00480

GnomAD3 exomes

AF:

0.0105

AC:

1087

AN:

103530

Hom.:

AF XY:

0.00991

AC XY:

592

AN XY:

59764

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00418

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000386

Gnomad FIN exome

AF:

0.0336

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.00921

GnomAD4 exome

AF:

0.0124

AC:

16196

AN:

1301780

Hom.:

130

Cov.:

AF XY:

0.0120

AC XY:

7676

AN XY:

640686

show subpopulations

Gnomad4 AFR exome

AF:

0.00152

Gnomad4 AMR exome

AF:

0.00522

Gnomad4 ASJ exome

AF:

0.00983

Gnomad4 EAS exome

AF:

0.0000337

Gnomad4 SAS exome

AF:

0.000258

Gnomad4 FIN exome

AF:

0.0287

Gnomad4 NFE exome

AF:

0.0135

Gnomad4 OTH exome

AF:

0.0121

GnomAD4 genome

AF:

0.00982

AC:

1488

AN:

151474

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

820

AN XY:

74040

show subpopulations

Gnomad4 AFR

AF:

0.00232

Gnomad4 AMR

AF:

0.0120

Gnomad4 ASJ

AF:

0.00981

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.0344

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.00475

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.00852

ESP6500AA

AF:

0.00457

AC:

ESP6500EA

AF:

0.0111

AC:

ExAC

AF:

0.00757

AC:

822

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	Allele frequency greater than expected for disorder (BS1); Homozygotes reported in GnomAD (BS2); Classified benign by a reputable source (BP6) -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 16, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	This variant is associated with the following publications: (PMID: 17458871, 21228398, 22133300) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ARSB: BS1, BS2 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2014	- -

ARSB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Benign

4.4

DANN

Benign

0.82

DEOGEN2

Benign

0.32

T;.;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.33

T;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.34

N;N;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.39

N;N;N;D

REVEL

Uncertain

0.35

Sift

Benign

0.76

T;T;T;.

Sift4G

Benign

0.31

T;T;T;.

Polyphen

0.0020

B;.;.;.

Vest4

0.54

MPC

1.5

ClinPred

0.0025

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.026

gMVP

0.55

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