chr22-50625988-T-C

Variant names:

Variant summary

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

The NM_000487.6(ARSA):c.1055A>G(p.Asn352Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,576,320 control chromosomes in the GnomAD database, including 18,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★).

Frequency

Genomes: 𝑓 0.19 ( 3436 hom., cov: 34)

Exomes 𝑓: 0.14 ( 15535 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts U:1B:15O:3

Conservation

PhyloP100: 1.46

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014927089).

BP6

Variant 22-50625988-T-C is Benign according to our data. Variant chr22-50625988-T-C is described in ClinVar as [Likely_benign, other]. Clinvar id is 3050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50625988-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.1055A>G	p.Asn352Ser	missense_variant	Exon 6 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.1055A>G	p.Asn352Ser	missense_variant	Exon 6 of 8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

AF:

0.192

AC:

29196

AN:

152016

Hom.:

3416

Cov.:

show subpopulations

Gnomad AFR

AF:

0.329

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.240

Gnomad ASJ

AF:

0.138

Gnomad EAS

AF:

0.164

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.0660

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.126

Gnomad OTH

AF:

0.187

GnomAD3 exomes

AF:

0.165

AC:

31196

AN:

188538

Hom.:

3261

AF XY:

0.158

AC XY:

15952

AN XY:

100644

show subpopulations

Gnomad AFR exome

AF:

0.337

Gnomad AMR exome

AF:

0.298

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.173

Gnomad SAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.0631

Gnomad NFE exome

AF:

0.127

Gnomad OTH exome

AF:

0.158

GnomAD4 exome

AF:

0.138

AC:

196120

AN:

1424186

Hom.:

15535

Cov.:

AF XY:

0.137

AC XY:

96518

AN XY:

704492

show subpopulations

Gnomad4 AFR exome

AF:

0.351

Gnomad4 AMR exome

AF:

0.294

Gnomad4 ASJ exome

AF:

0.139

Gnomad4 EAS exome

AF:

0.164

Gnomad4 SAS exome

AF:

0.147

Gnomad4 FIN exome

AF:

0.0646

Gnomad4 NFE exome

AF:

0.127

Gnomad4 OTH exome

AF:

0.147

GnomAD4 genome

AF:

0.192

AC:

29259

AN:

152134

Hom.:

3436

Cov.:

AF XY:

0.188

AC XY:

14013

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.329

Gnomad4 AMR

AF:

0.240

Gnomad4 ASJ

AF:

0.138

Gnomad4 EAS

AF:

0.164

Gnomad4 SAS

AF:

0.146

Gnomad4 FIN

AF:

0.0660

Gnomad4 NFE

AF:

0.126

Gnomad4 OTH

AF:

0.192

Alfa

AF:

0.144

Hom.:

3233

Bravo

AF:

0.215

TwinsUK

AF:

0.138

AC:

510

ALSPAC

AF:

0.119

AC:

458

ESP6500AA

AF:

0.299

AC:

1305

ESP6500EA

AF:

0.123

AC:

1050

ExAC

AF:

0.132

AC:

15352

Asia WGS

AF:

0.195

AC:

680

AN:

3478

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Uncertain:1Benign:15Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Benign:7Other:2

Dec 10, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Gelb Laboratory, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

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. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Benign - Stand Alone, for Metachromatic leukodystrophy, autosomal recessive. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (https://www.ncbi.nlm.nih.gov/pubmed/11941485) (https://www.ncbi.nlm.nih.gov/pubmed/2574462). -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 1997

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Benign:5

Clinical Genetics, Academic Medical Center

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

- -

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

- -

not provided

Benign:3Other:1

Jul 24, 2018

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Nov 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 2574462, 21648305, 8897113, 30026549, 32437521, 26577183, 31670782, 32470555, 31312839, 31694723, 23581857) -

Oct 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Metachromatic leukodystrophy, juvenile type

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

ClinVar reports this variant as a Pseudodeficiency allele from ClinVar. Homozygosity for the p.Asn350Ser variant alone results in 50% or more of the mean control ARSA enzyme activity in leukocytes.Â¬â€ Allele frequency is common in at least one population database (frequency: 39.478% in ExAC) based on the frequency threshold of 1.151% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.This variant is interpreted as Benign - Stand Alone, for Metachromatic leukodystrophy, autosomal recessive. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (https://www.ncbi.nlm.nih.gov/pubmed/11941485) (https://www.ncbi.nlm.nih.gov/pubmed/2574462). (ClinVar: SIB Swiss Institute of Bioinformatics) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;T;T;.;T

Eigen

Benign

-0.088

Eigen_PC

Benign

0.082

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

.;.;.;D;D

MetaRNN

Benign

0.0015

T;T;T;T;T

MetaSVM

Benign

-1.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.23

T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T

Vest4

0.15

ClinPred

0.011

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.46

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