chr22-50627329-C-T

Position:

chr22-50627329-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000487.6(ARSA):c.302G>A(p.Gly101Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 1,435,736 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. G101C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 4.83

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 Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50627330-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2191760.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 22-50627329-C-T is Pathogenic according to our data. Variant chr22-50627329-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50627329-C-T is described in Lovd as [Pathogenic]. Variant chr22-50627329-C-T is described in Lovd as [Pathogenic]. Variant chr22-50627329-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6 linkuse as main transcript	c.302G>A	p.Gly101Asp	missense_variant	2/8	ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10 linkuse as main transcript	c.302G>A	p.Gly101Asp	missense_variant	2/8	1	NM_000487.6	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000153

AC:

AN:

195792

Hom.:

AF XY:

0.0000186

AC XY:

AN XY:

107252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000680

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000239

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000132

AC:

AN:

1435736

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

712372

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000285

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000636

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000314

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:4Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 24, 2021	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 03, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 03, 2023	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 101 of the ARSA protein (p.Gly101Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 1673291, 20890085, 26131420). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3053). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSA function (PMID: 1673291). This variant disrupts the p.Gly101 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10477432, 26553228, 27374302, 27779215, 30057904). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 25, 2018	Variant summary: ARSA c.302G>A (p.Gly101Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 47324 control chromosomes (gnomAD). The variant, c.302G>A, has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Kondo_1991, Han_2015, Kurosawa_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kondo_1991). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ARSA: PM1, PM2, PM3, PM5, PP4, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2016	- -

Metachromatic leukodystrophy, adult type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;T;T;.;T

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

.;.;.;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.7

D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.98

MVP

0.99

ClinPred

0.98

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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