chrX-2938114-C-G

Variant names:

• chrX-2938114-C-G
• rs35143646
• NM_000047.3:c.1270G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000047.3(ARSL):​c.1270G>C​(p.Gly424Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G424S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.69
• Publications: 32 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	NM_000047.3	MANE Select	c.1270G>C	p.Gly424Arg	missense	Exon 9 of 11	NP_000038.2
	ARSL	NM_001282628.2		c.1345G>C	p.Gly449Arg	missense	Exon 10 of 12	NP_001269557.1
	ARSL	NM_001369080.1		c.1345G>C	p.Gly449Arg	missense	Exon 10 of 12	NP_001356009.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	ENST00000381134.9	TSL:1 MANE Select	c.1270G>C	p.Gly424Arg	missense	Exon 9 of 11	ENSP00000370526.3
	ARSL	ENST00000545496.6	TSL:2	c.1345G>C	p.Gly449Arg	missense	Exon 10 of 12	ENSP00000441417.1
	ARSL	ENST00000672027.1		c.1345G>C	p.Gly449Arg	missense	Exon 10 of 12	ENSP00000500220.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 62

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	2.0	M
PhyloP100		2.7
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.010	D
Sift4G	Benign	0.087	T
Polyphen		1.0	D
Vest4		0.31
MutPred		0.72		Gain of methylation at G449 (P = 0.1755)
MVP		0.95
MPC		1.4
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.55
gMVP		0.97
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs35143646; hg19: chrX-2856155;