rs122460155

Positions:

• chrX-2935127-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000047.3(ARSL):​c.1475G>A​(p.Cys492Tyr) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.56

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant X-2935127-C-T is Pathogenic according to our data. Variant chrX-2935127-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-2935127-C-T is described in Lovd as [Pathogenic]. Variant chrX-2935127-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSL	NM_000047.3	c.1475G>A	p.Cys492Tyr	missense_variant	11/11	ENST00000381134.9	NP_000038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSL	ENST00000381134.9	c.1475G>A	p.Cys492Tyr	missense_variant	11/11	1	NM_000047.3	ENSP00000370526	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked chondrodysplasia punctata 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 12, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Uncertain	0.76	D;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.6	.;.;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.88
MutPred		0.75		Gain of phosphorylation at C517 (P = 0.0764);.;.;
MVP		0.94
MPC		1.7
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.85

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: rs122460155; hg19: chrX-2853168;