rs2071421

Positions:

chr22-50625988-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N352H) has been classified as Uncertain significance.

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 -18 ACMG points.

PM1

In a disulfide_bond (size 114) in uniprot entity ARSA_HUMAN there are 144 pathogenic changes around while only 5 benign (97%) in NM_000487.6

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/exons	MANE	UniProt
ARSA	NM_000487.6 linkuse as main transcript	c.1055A>G	p.Asn352Ser	missense_variant	6/8	ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10 linkuse as main transcript	c.1055A>G	p.Asn352Ser	missense_variant	6/8	1	NM_000487.6	P1

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:6Other:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 10, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	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). -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3Other:1

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 11, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2021	This variant is associated with the following publications: (PMID: 2574462, 21648305, 8897113, 30026549, 32437521, 26577183, 31670782, 32470555, 31312839, 31694723, 23581857) -

Metachromatic leukodystrophy, juvenile type

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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) -

ARYLSULFATASE A POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Dec 01, 1997

- -

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

MutationTaster

Benign

0.034

P;P;P;P;P;P;P

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