chrX-2934875-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000047.3(ARSL):​c.1727C>T​(p.Pro576Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,196,620 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 0.000011 ( 0 hom. 1 hem. )

Consequence

ARSL
NM_000047.3 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.501
Variant links:
Genes affected
ARSL (HGNC:719): (arylsulfatase L) Arylsulfatase E is a member of the sulfatase family. It is glycosylated postranslationally and localized to the golgi apparatus. Sulfatases are essential for the correct composition of bone and cartilage matrix. X-linked chondrodysplasia punctata, a disease characterized by abnormalities in cartilage and bone development, has been linked to mutations in this gene. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on the Y chromosome. [provided by RefSeq, Sep 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.052426487).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARSLNM_000047.3 linkc.1727C>T p.Pro576Leu missense_variant Exon 11 of 11 ENST00000381134.9 NP_000038.2 P51690

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARSLENST00000381134.9 linkc.1727C>T p.Pro576Leu missense_variant Exon 11 of 11 1 NM_000047.3 ENSP00000370526.3 P51690

Frequencies

GnomAD3 genomes
AF:
0.00000900
AC:
1
AN:
111086
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33296
show subpopulations
Gnomad AFR
AF:
0.0000327
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000571
AC:
1
AN:
175220
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
60508
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000377
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000111
AC:
12
AN:
1085482
Hom.:
0
Cov.:
29
AF XY:
0.00000284
AC XY:
1
AN XY:
352732
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000576
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:
0.0000120
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000900
AC:
1
AN:
111138
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33358
show subpopulations
Gnomad4 AFR
AF:
0.0000326
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:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Chondrodysplasia punctata, brachytelephalangic, autosomal Uncertain:1
Feb 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 576 of the ARSE protein (p.Pro576Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ARSE-related conditions. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARSE protein function. 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
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
0.018
DANN
Benign
0.56
DEOGEN2
Benign
0.42
T;.;T
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.24
T;T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.052
T;T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
1.0
.;.;L
PrimateAI
Benign
0.38
T
PROVEAN
Benign
0.050
N;N;N
REVEL
Benign
0.10
Sift
Benign
0.28
T;T;T
Sift4G
Benign
0.29
T;T;T
Polyphen
0.0030
B;B;B
Vest4
0.13
MutPred
0.52
Loss of glycosylation at P601 (P = 0.0558);.;.;
MVP
0.95
MPC
0.45
ClinPred
0.023
T
GERP RS
-3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.037
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs746132186; hg19: chrX-2852916; API