rs6151415

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000487.6(ARSA):c.585G>T(p.Trp195Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 1,613,172 control chromosomes in the GnomAD database, including 4,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 275 hom., cov: 33)

Exomes 𝑓: 0.070 ( 4138 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.05

Publications

27 publications found

Variant links:

Genes affected

ARSA (HGNC:713): (arylsulfatase A) The protein encoded by this gene hydrolyzes cerebroside sulfate to cerebroside and sulfate. Defects in this gene lead to metachromatic leucodystrophy (MLD), a progressive demyelination disease which results in a variety of neurological symptoms and ultimately death. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2010]

ARSA Gene-Disease associations (from GenCC):

metachromatic leukodystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
metachromatic leukodystrophy, juvenile form
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ARSA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000487.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 159 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.38013 (below the threshold of 3.09). Trascript score misZ: -0.56919 (below the threshold of 3.09). GenCC associations: The gene is linked to metachromatic leukodystrophy, juvenile form, metachromatic leukodystrophy.

BP4

Computational evidence support a benign effect (MetaRNN=0.004769802).

BP6

Variant 22-50626933-C-A is Benign according to our data. Variant chr22-50626933-C-A is described in ClinVar as Benign. ClinVar VariationId is 93125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.585G>T	p.Trp195Cys	missense_variant	Exon 3 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10 link	c.585G>T	p.Trp195Cys	missense_variant	Exon 3 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes

AF:

0.0511

AC:

7779

AN:

152216

Hom.:

276

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0340

Gnomad ASJ

AF:

0.0810

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0780

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0772

Gnomad OTH

AF:

0.0507

GnomAD2 exomes

AF:

0.0529

AC:

13189

AN:

249174

AF XY:

0.0535

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.0277

Gnomad ASJ exome

AF:

0.0750

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.0752

Gnomad NFE exome

AF:

0.0768

Gnomad OTH exome

AF:

0.0586

GnomAD4 exome

AF:

0.0703

AC:

102707

AN:

1460838

Hom.:

4138

Cov.:

AF XY:

0.0691

AC XY:

50188

AN XY:

726720

show subpopulations

African (AFR)

AF:

0.0110

AC:

367

AN:

33480

American (AMR)

AF:

0.0281

AC:

1258

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0691

AC:

1805

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0224

AC:

1933

AN:

86256

European-Finnish (FIN)

AF:

0.0718

AC:

3766

AN:

52476

Middle Eastern (MID)

AF:

0.0517

AC:

298

AN:

5768

European-Non Finnish (NFE)

AF:

0.0806

AC:

89645

AN:

1111936

Other (OTH)

AF:

0.0601

AC:

3629

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

6869

13739

20608

27478

34347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3266

6532

9798

13064

16330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0511

AC:

7778

AN:

152334

Hom.:

275

Cov.:

AF XY:

0.0502

AC XY:

3738

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0150

AC:

623

AN:

41594

American (AMR)

AF:

0.0339

AC:

519

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0810

AC:

281

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0153

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0780

AC:

828

AN:

10620

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0772

AC:

5249

AN:

68018

Other (OTH)

AF:

0.0502

AC:

106

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

394

788

1183

1577

1971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0676

Hom.:

1033

Bravo

AF:

0.0458

TwinsUK

AF:

0.0747

AC:

277

ALSPAC

AF:

0.0825

AC:

318

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.0771

AC:

663

ExAC

AF:

0.0527

AC:

6402

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0796

EpiControl

AF:

0.0787

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 23, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Metachromatic leukodystrophy

Benign:4

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 25, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31836585, 28670130, 8897113) -

Citrullinemia

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T;T;.;T

Eigen

Benign

0.0048

Eigen_PC

Benign

0.041

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.86

.;.;.;D;D

MetaRNN

Benign

0.0048

T;T;T;T;T

MetaSVM

Benign

-0.32

PhyloP100

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.73

N;N;N;N;N

REVEL

Uncertain

0.42

Sift

Benign

0.036

D;D;D;D;D

Sift4G

Uncertain

0.032

D;D;D;T;D

Vest4

0.49

ClinPred

0.010

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.90

Mutation Taster

=71/29

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over