rs74315464

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The ENST00000216124.10(ARSA):​c.470C>T​(p.Pro157Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000748 in 1,604,200 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P157R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

ARSA
ENST00000216124.10 missense

Scores

5
8
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2O:1

Conservation

PhyloP100: 7.32
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000216124.10
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-50627048-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3067.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.915
PP5
Variant 22-50627048-G-A is Pathogenic according to our data. Variant chr22-50627048-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68137.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, not_provided=1}. Variant chr22-50627048-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARSANM_000487.6 linkuse as main transcriptc.470C>T p.Pro157Leu missense_variant 3/8 ENST00000216124.10 NP_000478.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARSAENST00000216124.10 linkuse as main transcriptc.470C>T p.Pro157Leu missense_variant 3/81 NM_000487.6 ENSP00000216124 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000758
AC:
11
AN:
1451980
Hom.:
0
Cov.:
33
AF XY:
0.00000832
AC XY:
6
AN XY:
720750
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000995
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Other:1
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Likely pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicDec 28, 2021PP4, PM2, PM3 -
Metachromatic leukodystrophy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaAug 15, 2018The ARSA c.470C>T (p.Pro157Leu) variant is a missense variant that has been reported in a compound heterozygous state in one individual with juvenile arylsulfatase A deficiency (Eng et al. 2003). The p.Pro157Leu variant was not found in 50 control individuals but is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database. This frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. The evidence for this variant is limited. The p.Pro157Leu variant is thus classified as a variant of unknown significance but suspicious for pathogenicity for arylsulfatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 12, 2021This sequence change replaces proline with leucine at codon 157 of the ARSA protein (p.Pro157Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 14517960). This variant is also known as P155L. ClinVar contains an entry for this variant (Variation ID: 68137). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
T;T;T;.;T
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
.;.;.;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D
MetaSVM
Uncertain
0.45
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-5.2
D;D;D;D;D
REVEL
Pathogenic
0.73
Sift
Benign
0.15
T;T;T;D;T
Sift4G
Benign
0.11
T;T;T;T;T
Vest4
0.94
MVP
0.98
ClinPred
0.98
D
GERP RS
4.2
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs74315464; hg19: chr22-51065476; API