22-50625182-C-T

Variant names:

• chr22-50625182-C-T
• rs6151428
• NM_000487.6:c.1493G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000487.6(ARSA):​c.1493G>A​(p.Arg498His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 1,594,468 control chromosomes in the GnomAD database, including 1,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R498P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (303 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1269 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.43
• Publications: 13 publications found

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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000487.6
• 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=0.0019086301).
• BP6: Variant 22-50625182-C-T is Benign according to our data. Variant chr22-50625182-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.1493G>A	p.Arg498His	missense_variant	Exon 8 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.1493G>A	p.Arg498His	missense_variant	Exon 8 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8071 AN: 152204 Hom.: 301 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00876

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0535

GnomAD2 exomes AF: 0.0305 AC: 6634 AN: 217596 AF XY: 0.0296

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0261

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00909

Gnomad NFE exome AF: 0.0396

Gnomad OTH exome AF: 0.0303

GnomAD4 exome AF: 0.0373 AC: 53731 AN: 1442146 Hom.: 1269 Cov.: 32 AF XY: 0.0362 AC XY: 25901 AN XY: 715820

African (AFR) AF: 0.106 AC: 3510 AN: 33194

American (AMR) AF: 0.0275 AC: 1175 AN: 42702

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 487 AN: 25466

East Asian (EAS) AF: 0.0000766 AC: 3 AN: 39170

South Asian (SAS) AF: 0.00655 AC: 553 AN: 84374

European-Finnish (FIN) AF: 0.0104 AC: 517 AN: 49700

Middle Eastern (MID) AF: 0.0220 AC: 121 AN: 5500

European-Non Finnish (NFE) AF: 0.0409 AC: 45121 AN: 1102596

Other (OTH) AF: 0.0377 AC: 2244 AN: 59444

GnomAD4 genome AF: 0.0530 AC: 8080 AN: 152322 Hom.: 303 Cov.: 32 AF XY: 0.0500 AC XY: 3724 AN XY: 74494

African (AFR) AF: 0.100 AC: 4160 AN: 41560

American (AMR) AF: 0.0453 AC: 694 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00434 AC: 21 AN: 4834

European-Finnish (FIN) AF: 0.00876 AC: 93 AN: 10618

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0411 AC: 2795 AN: 68020

Other (OTH) AF: 0.0529 AC: 112 AN: 2116

Alfa AF: 0.0330 Hom.: 57

Bravo AF: 0.0583

TwinsUK AF: 0.0421 AC: 156

ALSPAC AF: 0.0389 AC: 150

ESP6500AA AF: 0.0884 AC: 384

ESP6500EA AF: 0.0381 AC: 325

ExAC AF: 0.0297 AC: 3586

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 15, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.1493G>A (p.Arg498His) in the ARSA gene is a missense change that involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of gnomAD project at an allele frequency of 0.0323 (7925/ 245028 chrs tested), predominantly in individuals of African descent (0.1; 2138/ 21170 chrs, including 119 homozygotes). These frequencies exceed the maximal expected allele frequency for a pathogenic variant in this gene (0.0028). In functional studies, an enzymatic assay performed on platelet lysates from an individual homozygous for R498H showed normal values comparative with wild-type, therefore the variant is considered to be functionally neutral. In addition, several reputable databases/diagnostic centers classified the variant of interest as Benign/likely Benign. Taking together, the variant was classified as Benign. -

Sep 24, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Apr 18, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Metachromatic leukodystrophy Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.4
DANN	Benign	0.91
DEOGEN2	Benign	0.22	T;T;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.18	.;.;.;T;T
MetaRNN	Benign	0.0019	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		1.4
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.11	N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.58	T;T;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T
Vest4		0.051
ClinPred		0.00099	T
GERP RS		-0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.43
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6151428; hg19: chr22-51063610;