rs122460152

Variant names:

• chrX-2953224-C-T
• rs122460152
• NM_000047.3:c.349G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000047.3(ARSL):​c.349G>A​(p.Gly117Arg) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.82

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant X-2953224-C-T is Pathogenic according to our data. Variant chrX-2953224-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-2953224-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSL	NM_000047.3	c.349G>A	p.Gly117Arg	missense_variant	Exon 5 of 11	ENST00000381134.9	NP_000038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSL	ENST00000381134.9	c.349G>A	p.Gly117Arg	missense_variant	Exon 5 of 11	1	NM_000047.3	ENSP00000370526.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked chondrodysplasia punctata 1 Pathogenic:2

May 23, 2023

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Nov 01, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a significant reduction in ARSE activity compared to wild-type (Matos-Miranda et al., 2013); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26526591, 7720070, 23470839) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;D;.
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	.;.;L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0090	D;T;D;.
Polyphen		0.99	D;D;D;.
Vest4		0.70
MutPred		0.78		Gain of MoRF binding (P = 0.0147);.;.;.;
MVP		0.94
MPC		1.4
ClinPred		0.97	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.94

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

Other links and lift over

dbSNP: rs122460152; hg19: chrX-2871265; COSMIC: COSV66964820;