rs199476390

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1PM2PP3PP5

The NM_000487.6(ARSA):c.942G>T(p.Glu314Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,458,154 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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: -0.717

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS1

Transcript NM_000487.6 (ARSA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

PP5

Variant 22-50626191-C-A is Pathogenic according to our data. Variant chr22-50626191-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68166.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, not_provided=1}. Variant chr22-50626191-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.942G>T	p.Glu314Asp	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.942G>T	p.Glu314Asp	missense_variant	Exon 5 of 8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000207

AC:

AN:

241008

Hom.:

AF XY:

0.0000306

AC XY:

AN XY:

130704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000461

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000206

AC:

AN:

1458154

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

725078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:2Uncertain:1

Feb 15, 2023

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.942G>T (p.Glu314Asp) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 241008 control chromosomes (gnomAD). c.942G>T has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (ML) or features of ML (example: Bohringer_2017 and Herman_2000). These data do not allow any conclusion about variant significance. Multiple publications reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Bohringer_2017 and Herman_2000). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 314 of the ARSA protein (p.Glu314Asp). This variant is present in population databases (rs199476390, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 10751093). This variant is also known as E312D. ClinVar contains an entry for this variant (Variation ID: 68166). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARSA protein function. Experimental studies have shown that this missense change affects ARSA function (PMID: 10751093, 28762252). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of 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

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T;T;.;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.071

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.91

.;.;.;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.75

D;D;D;D;D

MetaSVM

Uncertain

0.63

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.1

N;N;N;N;N

REVEL

Pathogenic

0.73

Sift

Benign

0.35

T;T;T;T;T

Sift4G

Benign

0.48

T;T;T;T;T

Vest4

0.66

MVP

0.91

ClinPred

0.64

GERP RS

0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.97

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

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