dbSNP rs1135401757: ARSA:p.His425Arg (chr22-50625401-T-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_000487.6(ARSA):c.1274A>G(p.His425Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,446,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.67

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a strand (size 9) in uniprot entity ARSA_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000487.6

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-50625401-T-C is Pathogenic according to our data. Variant chr22-50625401-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.1274A>G	p.His425Arg	missense_variant	Exon 8 of 8	ENST00000216124.10	NP_000478.3	P15289A0A0C4DFZ2B4DVI5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10 link	c.1274A>G	p.His425Arg	missense_variant	Exon 8 of 8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1446752

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717480

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.07e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:3

May 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2017

Neurometabolisches Labor, University hospital Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 30, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ARSA c.1274A>G (p.His425Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 241050 control chromosomes (gnomAD). c.1274A>G has been reported in the literature in an individual affected with Metachromatic Leukodystrophy (Bohringer_2017). These data do not allow any conclusion about variant significance. This publication also reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity. The following publication has been ascertained in the context of this evaluation (PMID: 28762252). ClinVar contains an entry for this variant (Variation ID: 431090). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T;T;.;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

.;.;.;T;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.61

D;D;D;D;D

MetaSVM

Uncertain

0.75

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.0

D;D;D;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0040

D;D;D;D;D

Sift4G

Uncertain

0.021

D;D;D;D;D

Vest4

0.32

MVP

0.98

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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