rs527640350

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000487.6(ARSA):c.674A>G(p.Tyr225Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,612,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1O:1

Conservation

PhyloP100: 3.16

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.879

PP5

Variant 22-50626844-T-C is Pathogenic according to our data. Variant chr22-50626844-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431088.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.674A>G	p.Tyr225Cys	missense_variant	Exon 3 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.674A>G	p.Tyr225Cys	missense_variant	Exon 3 of 8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000638

AC:

AN:

250758

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461008

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151934

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:3Uncertain:1Other:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 225 of the ARSA protein (p.Tyr225Cys). This variant is present in population databases (rs527640350, gnomAD 0.05%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 28762252). ClinVar contains an entry for this variant (Variation ID: 431088). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ARSA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSA function (PMID: 28762252). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Gelb Laboratory, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Nov 21, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2017

Neurometabolisches Labor, University hospital Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ARSA c.674A>G (p.Tyr225Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR000917) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250758 control chromosomes (gnomAD). This frequency is not higher than the maximum estimated for a pathogenic variant in ARSA causing Metachromatic Leukodystrophy (0.0028), allowing no conclusion about variant significance. The variant, c.674A>G, has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (e.g. Bohringer_2017, Santhanakumaran_2022). These data indicate that the variant may be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in <10% of normal activity in in vitro expression system, and in patient derived cells (e.g. Bohringer_2017, Santhanakumaran_2022). The following publications have been ascertained in the context of this evaluation (PMID: 28762252, 36240581). ClinVar contains an entry for this variant (Variation ID: 431088). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;T;T;.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

.;.;.;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.88

D;D;D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.8

D;D;D;D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Vest4

0.84

MVP

0.96

ClinPred

0.77

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.93

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