22-50627213-G-C

Position:

chr22-50627213-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000487.6(ARSA):c.418C>G(p.His140Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1O:2

Conservation

PhyloP100: 1.93

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:

ARSA (HGNC:):

ARSA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-50627213-G-C is Pathogenic according to our data. Variant chr22-50627213-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50627213-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6 linkuse as main transcript	c.418C>G	p.His140Asp	missense_variant	2/8	ENST00000216124.10	NP_000478.3	P15289A0A0C4DFZ2B4DVI5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10 linkuse as main transcript	c.418C>G	p.His140Asp	missense_variant	2/8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000126

AC:

AN:

238808

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000945

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1459960

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:3Uncertain:1Other:1

Uncertain significance, flagged submission	clinical testing	Counsyl	May 26, 2017	- -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 15, 2021	Variant summary: ARSA c.418C>G (p.His140Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 238808 control chromosomes (gnomAD). c.418C>G has been reported in the literature in at least one individual affected with Metachromatic Leukodystrophy (Biffi_2008). Experimental evidence evaluating an impact on protein function demonstrated the variant results in low residual enzyme activity (Cesani_2009). One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic and another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 07, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ARSA function (PMID: 19606494). 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) has been performed at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 68132). This variant is also known as c.412C>G (His138Asp) in literature. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18786133, 33855715; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199476358, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 140 of the ARSA protein (p.His140Asp). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 07, 2022	- -

not provided

Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.26

T;T;T;.;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

.;.;.;D;D

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.65

D;D;D;D;D

MetaSVM

Uncertain

-0.16

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.76

N;N;N;N;N

REVEL

Uncertain

0.55

Sift

Benign

0.37

T;T;T;T;T

Sift4G

Benign

0.78

T;T;T;T;T

Vest4

0.55

MVP

0.79

ClinPred

0.16

GERP RS

3.7

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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