dbSNP rs74315475: ARSA:p.Asp337Val (chr22-50626033-T-A) – ACMG Classification: Pathogenic (21 pts)

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000487.6(ARSA):c.1010A>T(p.Asp337Val) variant causes a missense change. The variant allele was found at a frequency of 0.000075 in 1,587,406 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000836843: Experimental studies have shown that this missense change affects ARSA function (PMID:8723680)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D337D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 5.96

Publications

8 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ARSA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 21 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000836843: Experimental studies have shown that this missense change affects ARSA function (PMID: 8723680).; SCV001360433: Experimental evidence evaluating an impact on protein function demonstrated the variant to cause a complete loss of catalytic activity of the enzyme (Hess_1996).; SCV000490408: Published functional studies demonstrate a damaging effect with no functional arylsulfatase A activity (Hess et al., 1996); SCV002563738: PS3:Supporting

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000487.6

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 22-50626033-T-A is Pathogenic according to our data. Variant chr22-50626033-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000487.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARSA	NM_000487.6	MANE Select	c.1010A>T	p.Asp337Val	missense	Exon 6 of 8	NP_000478.3
ARSA	NM_001085425.3		c.1010A>T	p.Asp337Val	missense	Exon 7 of 9	NP_001078894.2	A0A0C4DFZ2
ARSA	NM_001085426.3		c.1010A>T	p.Asp337Val	missense	Exon 7 of 9	NP_001078895.2	A0A0C4DFZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARSA	ENST00000216124.10	TSL:1 MANE Select	c.1010A>T	p.Asp337Val	missense	Exon 6 of 8	ENSP00000216124.5	A0A0C4DFZ2
ARSA	ENST00000356098.9	TSL:1	c.1010A>T	p.Asp337Val	missense	Exon 7 of 9	ENSP00000348406.5	A0A0C4DFZ2
ARSA	ENST00000395619.3	TSL:5	c.1010A>T	p.Asp337Val	missense	Exon 7 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000343

AC:

AN:

204330

AF XY:

0.0000273

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000655

Gnomad OTH exome

AF:

0.000193

GnomAD4 exome

AF:

0.0000766

AC:

110

AN:

1435340

Hom.:

Cov.:

AF XY:

0.0000773

AC XY:

AN XY:

711326

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33358

American (AMR)

AF:

0.00

AC:

AN:

38228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25494

East Asian (EAS)

AF:

0.00

AC:

AN:

38844

South Asian (SAS)

AF:

0.00

AC:

AN:

82088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0000935

AC:

103

AN:

1101068

Other (OTH)

AF:

0.000101

AC:

AN:

59648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41404

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000868

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000167

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Metachromatic leukodystrophy (9)

not provided (3)

Leukodystrophy (1)

METACHROMATIC LEUKODYSTROPHY, SEVERE (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

PhyloP100

6.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-8.9

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.99

MVP

0.98

ClinPred

1.0

GERP RS

5.5

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over