rs745884435
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000487.6(ARSA):c.418delC(p.His140IlefsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
ARSA
NM_000487.6 frameshift
NM_000487.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.93
Publications
8 publications found
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 leukodystrophyInheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
- metachromatic leukodystrophy, juvenile formInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-50627212-TG-T is Pathogenic according to our data. Variant chr22-50627212-TG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 370472.
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
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ARSA | MANE Select | c.418delC | p.His140IlefsTer8 | frameshift | Exon 2 of 8 | NP_000478.3 | |||
| ARSA | c.418delC | p.His140IlefsTer8 | frameshift | Exon 3 of 9 | NP_001078894.2 | A0A0C4DFZ2 | |||
| ARSA | c.418delC | p.His140IlefsTer8 | frameshift | Exon 3 of 9 | NP_001078895.2 | A0A0C4DFZ2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ARSA | TSL:1 MANE Select | c.418delC | p.His140IlefsTer8 | frameshift | Exon 2 of 8 | ENSP00000216124.5 | A0A0C4DFZ2 | ||
| ARSA | TSL:1 | c.418delC | p.His140IlefsTer8 | frameshift | Exon 3 of 9 | ENSP00000348406.5 | A0A0C4DFZ2 | ||
| ARSA | TSL:5 | c.418delC | p.His140IlefsTer8 | frameshift | Exon 3 of 9 | ENSP00000378981.3 | A0A0C4DFZ2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD2 exomes AF: 0.00000418 AC: 1AN: 239254 AF XY: 0.00000763 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
239254
AF XY:
Gnomad AFR exome
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Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460180Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 726356 show subpopulations
GnomAD4 exome
AF:
AC:
3
AN:
1460180
Hom.:
Cov.:
33
AF XY:
AC XY:
3
AN XY:
726356
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33470
American (AMR)
AF:
AC:
0
AN:
44606
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26088
East Asian (EAS)
AF:
AC:
0
AN:
39680
South Asian (SAS)
AF:
AC:
0
AN:
86166
European-Finnish (FIN)
AF:
AC:
0
AN:
52578
Middle Eastern (MID)
AF:
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
AC:
3
AN:
1111500
Other (OTH)
AF:
AC:
0
AN:
60328
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.408
Heterozygous variant carriers
0
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1
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2
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0.00
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0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
Pathogenic
VUS
Benign
Condition
3
1
-
Metachromatic leukodystrophy (4)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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