rs743616

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_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. 13/16 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 Pathogenic.

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:2

Conservation

PhyloP100: 0.122

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50625612-T-C is described in Lovd as [Pathogenic].

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 id is 21184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50625611-G-C is described in Lovd as [Benign].

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

GnomAD3 exomes

AF:

0.480

AC:

120494

AN:

251106

Hom.:

29962

AF XY:

0.483

AC XY:

65650

AN XY:

135860

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 SAS exome

AF:

0.423

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

Gnomad4 AFR exome

AF:

0.382

Gnomad4 AMR exome

AF:

0.420

Gnomad4 ASJ exome

AF:

0.417

Gnomad4 EAS exome

AF:

0.343

Gnomad4 SAS exome

AF:

0.428

Gnomad4 FIN exome

AF:

0.595

Gnomad4 NFE exome

AF:

0.546

Gnomad4 OTH exome

AF:

0.493

GnomAD4 genome

AF:

0.479

AC:

72803

AN:

151914

Hom.:

17902

Cov.:

AF XY:

0.481

AC XY:

35740

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.390

Gnomad4 AMR

AF:

0.454

Gnomad4 ASJ

AF:

0.430

Gnomad4 EAS

AF:

0.310

Gnomad4 SAS

AF:

0.421

Gnomad4 FIN

AF:

0.597

Gnomad4 NFE

AF:

0.540

Gnomad4 OTH

AF:

0.453

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Benign:6Other:2

May 28, 2019

Mendelics

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

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

- -

Jul 14, 2021

Genome-Nilou Lab

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

- -

Gelb Laboratory, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Mar 16, 2015

Eurofins Ntd Llc (ga)

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

May 31, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1 -

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) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

0.66

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

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

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

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