rs74315459

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000487.6(ARSA):c.931G>T(p.Gly311Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,232 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G311S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.01

Publications

10 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: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000487.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50626202-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3060.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 22-50626202-C-A is Pathogenic according to our data. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50626202-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 2727052.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.931G>T	p.Gly311Cys	missense_variant	Exon 5 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.931G>T	p.Gly311Cys	missense_variant	Exon 5 of 8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

244148

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant disrupts the p.Gly311 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8101038, 26462614, 28670130). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 311 of the ARSA protein (p.Gly311Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 30674982). This variant is also known as p.Gly309Cys. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D;D;.;D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

.;.;.;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.0

PhyloP100

6.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-8.9

D;D;D;D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.98

MVP

0.96

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.99

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over