22-50625182-C-T

Position:

chr22-50625182-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000216124.10(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. 13/16 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. R498L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.053 ( 303 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1269 hom. )

Consequence

ARSA
ENST00000216124.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 1.43

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 Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in ENST00000216124.10

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 [Likely_benign]. Clinvar id is 93120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50625182-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
ARSA	NM_000487.6 linkuse as main transcript	c.1493G>A	p.Arg498His	missense_variant	8/8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10 linkuse as main transcript	c.1493G>A	p.Arg498His	missense_variant	8/8	1	NM_000487.6	ENSP00000216124	P1

Frequencies

GnomAD3 genomes

AF:

0.0530

AC:

8071

AN:

152204

Hom.:

301

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0305

AC:

6634

AN:

217596

Hom.:

180

AF XY:

0.0296

AC XY:

3548

AN XY:

119784

show subpopulations

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 SAS exome

AF:

0.00630

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.:

AF XY:

0.0362

AC XY:

25901

AN XY:

715820

show subpopulations

Gnomad4 AFR exome

AF:

0.106

Gnomad4 AMR exome

AF:

0.0275

Gnomad4 ASJ exome

AF:

0.0191

Gnomad4 EAS exome

AF:

0.0000766

Gnomad4 SAS exome

AF:

0.00655

Gnomad4 FIN exome

AF:

0.0104

Gnomad4 NFE exome

AF:

0.0409

Gnomad4 OTH exome

AF:

0.0377

GnomAD4 genome

AF:

0.0530

AC:

8080

AN:

152322

Hom.:

303

Cov.:

AF XY:

0.0500

AC XY:

3724

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.100

Gnomad4 AMR

AF:

0.0453

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00434

Gnomad4 FIN

AF:

0.00876

Gnomad4 NFE

AF:

0.0411

Gnomad4 OTH

AF:

0.0529

Alfa

AF:

0.0296

Hom.:

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:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 15, 2017	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. -

Metachromatic leukodystrophy

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.47

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

LIST_S2

Benign

0.18

.;.;.;T;T

MetaRNN

Benign

0.0019

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.22

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

GERP RS

-0.95

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.43

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