rs122460153

Positions:

• chrX-2953241-C-G
• chrX-2953241-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.332G>C​(p.Arg111Pro) 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: 3.80

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, 0.959
• PP5: Variant X-2953241-C-G is Pathogenic according to our data. Variant chrX-2953241-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 11524.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-2953241-C-G is described in Lovd as [Pathogenic]. Variant chrX-2953241-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSL	NM_000047.3	c.332G>C	p.Arg111Pro	missense_variant	5/11	ENST00000381134.9	NP_000038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSL	ENST00000381134.9	c.332G>C	p.Arg111Pro	missense_variant	5/11	1	NM_000047.3	ENSP00000370526	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

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

Apr 07, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Uncertain	0.76	D;.;D;.
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	.;.;L;.
MutationTaster	Benign	0.25	A;A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.3	D;D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.038	D;T;T;T
Sift4G	Uncertain	0.041	D;D;T;.
Polyphen		0.42	B;B;P;.
Vest4		0.71
MutPred		0.71		Loss of MoRF binding (P = 6e-04);.;.;.;
MVP		0.92
MPC		1.0
ClinPred		0.33	T
GERP RS		2.6
Varity_R		0.75
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs122460153; hg19: chrX-2871282;