22-50625228-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_000487.6(ARSA):c.1447G>A(p.Glu483Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,609,656 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 3 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.137

Publications

3 publications found

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 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

ARSA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 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=0.0069256127).

BP6

Variant 22-50625228-C-T is Benign according to our data. Variant chr22-50625228-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198734.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0023 (351/152324) while in subpopulation AFR AF = 0.00678 (282/41576). AF 95% confidence interval is 0.00613. There are 1 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.1447G>A	p.Glu483Lys	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 link	c.1447G>A	p.Glu483Lys	missense_variant	Exon 8 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes

AF:

0.00232

AC:

353

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00683

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.000863

AC:

211

AN:

244416

AF XY:

0.000705

show subpopulations

Gnomad AFR exome

AF:

0.00691

Gnomad AMR exome

AF:

0.00105

Gnomad ASJ exome

AF:

0.00133

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000421

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000556

AC:

810

AN:

1457332

Hom.:

Cov.:

AF XY:

0.000515

AC XY:

373

AN XY:

724614

show subpopulations

African (AFR)

AF:

0.00700

AC:

234

AN:

33414

American (AMR)

AF:

0.00119

AC:

AN:

44454

Ashkenazi Jewish (ASJ)

AF:

0.000847

AC:

AN:

25976

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39636

South Asian (SAS)

AF:

0.000128

AC:

AN:

85984

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

51978

Middle Eastern (MID)

AF:

0.00313

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000342

AC:

380

AN:

1109982

Other (OTH)

AF:

0.00150

AC:

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00230

AC:

351

AN:

152324

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00678

AC:

282

AN:

41576

American (AMR)

AF:

0.00203

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68030

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000879

Hom.:

Bravo

AF:

0.00287

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00614

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000850

AC:

103

EpiCase

AF:

0.000600

EpiControl

AF:

0.000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Uncertain:1Benign:3

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Nov 11, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

May 22, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ARSA-related disorder

Benign:1

Apr 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.3

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.24

T;T;T;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.73

.;.;.;T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.0069

T;T;T;T;T

MetaSVM

Benign

-0.73

PhyloP100

-0.14

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.20

N;N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.81

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Vest4

0.12

MVP

0.50

ClinPred

0.00022

GERP RS

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.40

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over