rs199476366

Positions:

chr22-50626708-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000487.6(ARSA):c.737G>A(p.Arg246His) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,772 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. R246C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:2

Conservation

PhyloP100: 5.93

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 18 ACMG points.

PM1

In a helix (size 22) in uniprot entity ARSA_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) 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 chr22-50626709-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 22-50626708-C-T is Pathogenic according to our data. Variant chr22-50626708-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626708-C-T is described in Lovd as [Pathogenic]. Variant chr22-50626708-C-T 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.737G>A	p.Arg246His	missense_variant	4/8	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.737G>A	p.Arg246His	missense_variant	4/8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

251028

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00214

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 246 of the ARSA protein (p.Arg246His). This variant is present in population databases (rs199476366, gnomAD 0.006%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 9090526, 22993277, 25965562, 26462614). This variant is also known as p.Arg244His. ClinVar contains an entry for this variant (Variation ID: 68148). 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%. This variant disrupts the p.Arg246 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 2299327, 9090526), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 12, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 10, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 17, 2017	- -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -

not provided

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R244H using alternate nomenclature; This variant is associated with the following publications: (PMID: 22993277, 27289174, 9090526, 25965562, 23845948, 26462614) -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

T;T;T;.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;.;.;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.1

D;D;D;D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Vest4

0.91

MVP

0.98

ClinPred

0.99

GERP RS

5.4

gMVP

0.92

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

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