chrX-2953241-C-G

Variant names:

• chrX-2953241-C-G
• rs122460153
• NM_000047.3:c.332G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R111C) has been classified as Likely pathogenic.

• 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
• Publications: 5 publications found

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]

ARSL Gene-Disease associations (from GenCC):

• X-linked chondrodysplasia punctata 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000047.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-2953242-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 427005.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 VariationId is 11524.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000047.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	NM_000047.3	MANE Select	c.332G>C	p.Arg111Pro	missense	Exon 5 of 11	NP_000038.2	P51690
	ARSL	NM_001282628.2		c.407G>C	p.Arg136Pro	missense	Exon 6 of 12	NP_001269557.1	F5GYY5
	ARSL	NM_001369080.1		c.407G>C	p.Arg136Pro	missense	Exon 6 of 12	NP_001356009.1	F5GYY5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	ENST00000381134.9	TSL:1 MANE Select	c.332G>C	p.Arg111Pro	missense	Exon 5 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.407G>C	p.Arg136Pro	missense	Exon 6 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.407G>C	p.Arg136Pro	missense	Exon 6 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	X-linked chondrodysplasia punctata 1 (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L
PhyloP100		3.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.64
Sift	Benign	0.038	D
Sift4G	Uncertain	0.041	D
Polyphen		0.42	B
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs122460153; hg19: chrX-2871282;