rs199476363

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_000487.6(ARSA):c.290G>A(p.Ser97Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S97S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: -0.0160

Publications

2 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: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000487.6

PM2

Very rare variant in population databases, with high coverage;

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.1743769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.290G>A	p.Ser97Asn	missense_variant	Exon 2 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.290G>A	p.Ser97Asn	missense_variant	Exon 2 of 8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443920

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717118

African (AFR)

AF:

0.00

AC:

AN:

33250

American (AMR)

AF:

0.00

AC:

AN:

42106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25740

East Asian (EAS)

AF:

0.00

AC:

AN:

39034

South Asian (SAS)

AF:

0.00

AC:

AN:

84230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104806

Other (OTH)

AF:

0.00

AC:

AN:

59714

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ARSA c.290G>A (p.Ser97Asn) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 208510 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.290G>A has been reported in the literature in at least one compound heterozygous individual affected with infantile metachromatic leukodystrophy (e.g., Draghia_1997). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 9090526). ClinVar contains an entry for this variant (Variation ID: 68128). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Other:1

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Benign

6.3

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.22

T;T;T;.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.91

.;.;.;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.17

T;T;T;T;T

MetaSVM

Uncertain

-0.016

PhyloP100

-0.016

PrimateAI

Benign

0.41

PROVEAN

Benign

0.94

N;N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.75

T;T;T;T;T

Sift4G

Benign

0.94

T;T;T;T;T

Vest4

0.67

MVP

0.79

ClinPred

0.081

GERP RS

1.6

gMVP

0.75

Mutation Taster

=5/95

disease causing

(source)

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

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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