rs6151411
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001085428.3(ARSA):c.-8C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000934 in 1,606,416 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).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000083 ( 0 hom. )
Consequence
ARSA
NM_001085428.3 5_prime_UTR_premature_start_codon_gain
NM_001085428.3 5_prime_UTR_premature_start_codon_gain
Scores
9
6
2
Clinical Significance
Conservation
PhyloP100: 3.67
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.938
PP5
Variant 22-50627380-G-A is Pathogenic according to our data. Variant chr22-50627380-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556430.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Pathogenic=2, Likely_pathogenic=1}. Variant chr22-50627380-G-A is described in Lovd as [Pathogenic]. Variant chr22-50627380-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.251C>T | p.Pro84Leu | missense_variant | 2/8 | ENST00000216124.10 | NP_000478.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.251C>T | p.Pro84Leu | missense_variant | 2/8 | 1 | NM_000487.6 | ENSP00000216124.5 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000174 AC: 4AN: 229438Hom.: 0 AF XY: 0.0000237 AC XY: 3AN XY: 126552
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GnomAD4 exome AF: 0.00000825 AC: 12AN: 1454206Hom.: 0 Cov.: 33 AF XY: 0.0000111 AC XY: 8AN XY: 723108
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74354
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:3Uncertain:2Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 26, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 12, 2022 | Variant summary: ARSA c.251C>T (p.Pro84Leu) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 229438 control chromosomes (gnomAD). c.251C>T has been reported in the literature in multiple compound heterozygous individuals affected with Metachromatic Leukodystrophy (e.g. Biffi_2008, van Rappard_2016, Bohringer_2017, Hettiarachchi_2019, Beeerepoot_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 05, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 05, 2018 | The ARSA c.251C>T (p.Pro84Leu) missense variant, historically described as p.Pro82Leu, has been reported two in studies. Barth et al. (1995) describe a child with late infantile arylsulfatase A deficiency, also known as metachromatic leukodystrophy, in whom the p.Pro84Leu variant was identified in a heterozygous state. A second variant was not detected. In 2008, Biffi et al. reported a child with early juvenile arylsulfatase A deficiency in whom the p.Pro84Leu was identified in trans with a second missense variant. The p.Pro84Leu variant was absent from 110 control chromosomes from healthy individuals, and is reported at a frequency of 0.000077 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Pro84Leu variant is classified as 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 02, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the ARSA protein (p.Pro84Leu). This variant is present in population databases (rs6151411, gnomAD 0.004%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18786133, 28762252, 31694723). ClinVar contains an entry for this variant (Variation ID: 556430). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function with a positive predictive value of 95%. This variant disrupts the p.Pro84 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 30057904), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | in vitro | Gelb Laboratory, University of Washington | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;T;T;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Benign
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Vest4
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at