rs199476382

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000487.6(ARSA):​c.938G>T​(p.Arg313Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R313P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ARSA
NM_000487.6 missense

Scores

11
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 4.92
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 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-50626195-C-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARSANM_000487.6 linkc.938G>T p.Arg313Leu missense_variant Exon 5 of 8 ENST00000216124.10 NP_000478.3 P15289A0A0C4DFZ2B4DVI5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARSAENST00000216124.10 linkc.938G>T p.Arg313Leu missense_variant Exon 5 of 8 1 NM_000487.6 ENSP00000216124.5 A0A0C4DFZ2

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1458570
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
725370
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Metachromatic leukodystrophy Uncertain:2
-
3billion
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Different missense changes at the same codon (p.Arg313Gln, p.Arg313Gly, p.Arg313Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068165 / PMID: 26462614, 34490615, 7581401). Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline. -

Feb 06, 2023
Rare Genetic Disease Lab, Dept of Zoology, Government Postgraduate College Dargai Malakand, Higher Education Govt. of Khyber Pakhtunkhwa
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
D;D;D;.;D
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;.;.;D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-6.9
D;D;D;D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D
Vest4
0.97
MVP
0.97
ClinPred
1.0
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-51064623; API