X-2946031-C-G

Variant names:

• chrX-2946031-C-G
• NM_000047.3:c.958G>C
• ARSL p.Gly320Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000047.3(ARSL):​c.958G>C​(p.Gly320Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G320G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.93
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000047.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

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.958G>C	p.Gly320Arg	missense	Exon 7 of 11	NP_000038.2	P51690
	ARSL	NM_001282628.2		c.1033G>C	p.Gly345Arg	missense	Exon 8 of 12	NP_001269557.1	F5GYY5
	ARSL	NM_001369080.1		c.1033G>C	p.Gly345Arg	missense	Exon 8 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.958G>C	p.Gly320Arg	missense	Exon 7 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.1033G>C	p.Gly345Arg	missense	Exon 8 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.1033G>C	p.Gly345Arg	missense	Exon 8 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.9
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.94
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-2864072;