rs743616

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1PM5PP2BP4_StrongBP6_Very_StrongBA1

The NM_000487.6(ARSA):c.1178C>G(p.Thr393Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,612,938 control chromosomes in the GnomAD database, including 220,625 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict 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. T393A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.48 ( 17902 hom., cov: 32)

Exomes 𝑓: 0.52 ( 202723 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 0.122

Publications

61 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 -15 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000487.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50625611-GT-CC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1308665.

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=1.3175593E-5).

BP6

Variant 22-50625611-G-C is Benign according to our data. Variant chr22-50625611-G-C is described in ClinVar as Benign. ClinVar VariationId is 21184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.1178C>G	p.Thr393Ser	missense_variant	Exon 7 of 8	ENST00000216124.10	NP_000478.3	P15289A0A0C4DFZ2B4DVI5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10 link	c.1178C>G	p.Thr393Ser	missense_variant	Exon 7 of 8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72763

AN:

151796

Hom.:

17887

Cov.:

show subpopulations

Gnomad AFR

AF:

0.390

Gnomad AMI

AF:

0.647

Gnomad AMR

AF:

0.455

Gnomad ASJ

AF:

0.430

Gnomad EAS

AF:

0.310

Gnomad SAS

AF:

0.420

Gnomad FIN

AF:

0.597

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.540

Gnomad OTH

AF:

0.456

GnomAD2 exomes

AF:

0.480

AC:

120494

AN:

251106

AF XY:

0.483

show subpopulations

Gnomad AFR exome

AF:

0.384

Gnomad AMR exome

AF:

0.418

Gnomad ASJ exome

AF:

0.424

Gnomad EAS exome

AF:

0.291

Gnomad FIN exome

AF:

0.594

Gnomad NFE exome

AF:

0.540

Gnomad OTH exome

AF:

0.498

GnomAD4 exome

AF:

0.523

AC:

763470

AN:

1461024

Hom.:

202723

Cov.:

AF XY:

0.521

AC XY:

378298

AN XY:

726796

show subpopulations

African (AFR)

AF:

0.382

AC:

12798

AN:

33476

American (AMR)

AF:

0.420

AC:

18779

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.417

AC:

10896

AN:

26124

East Asian (EAS)

AF:

0.343

AC:

13632

AN:

39696

South Asian (SAS)

AF:

0.428

AC:

36883

AN:

86252

European-Finnish (FIN)

AF:

0.595

AC:

31508

AN:

52992

Middle Eastern (MID)

AF:

0.388

AC:

2237

AN:

5768

European-Non Finnish (NFE)

AF:

0.546

AC:

606998

AN:

1111628

Other (OTH)

AF:

0.493

AC:

29739

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

22321

44642

66962

89283

111604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16918

33836

50754

67672

84590

<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:

0.479

AC:

72803

AN:

151914

Hom.:

17902

Cov.:

AF XY:

0.481

AC XY:

35740

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.390

AC:

16141

AN:

41408

American (AMR)

AF:

0.454

AC:

6947

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.430

AC:

1491

AN:

3470

East Asian (EAS)

AF:

0.310

AC:

1597

AN:

5150

South Asian (SAS)

AF:

0.421

AC:

2031

AN:

4824

European-Finnish (FIN)

AF:

0.597

AC:

6305

AN:

10566

Middle Eastern (MID)

AF:

0.388

AC:

114

AN:

294

European-Non Finnish (NFE)

AF:

0.540

AC:

36636

AN:

67900

Other (OTH)

AF:

0.453

AC:

955

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1918

3837

5755

7674

9592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.511

Hom.:

6579

Bravo

AF:

0.463

TwinsUK

AF:

0.540

AC:

2004

ALSPAC

AF:

0.544

AC:

2095

ESP6500AA

AF:

0.394

AC:

1736

ESP6500EA

AF:

0.530

AC:

4560

ExAC

AF:

0.483

AC:

58673

Asia WGS

AF:

0.384

AC:

1337

AN:

3478

EpiCase

AF:

0.520

EpiControl

AF:

0.515

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Benign:6Other:1

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. -

Nov 18, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2017

SingHealth Duke-NUS Institute of Precision Medicine

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:6

Mar 16, 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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

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: 31694723, 29961769, 11941485, 1670590, 20220177) -

May 31, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

0.66

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.23

T;T;T;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.0024

.;.;.;T;T

MetaRNN

Benign

0.000013

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.12

PrimateAI

Benign

0.36

PROVEAN

Benign

0.13

N;N;N;N;N

REVEL

Benign

0.29

Sift

Benign

0.47

T;T;T;T;T

Sift4G

Benign

0.41

T;T;T;T;T

Vest4

0.031

ClinPred

0.0040

GERP RS

-0.029

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.45

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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