NM_000047.3:c.119T>G

Variant names:

Variant summary

Our verdict is The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_Supporting

The NM_000047.3(ARSL):c.119T>G (p.Ile40Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000892 (AC=1) in the gnomAD database across 112,141 control chromosomes, including 1 hemizygote. The grpmax filtering allele frequency (95% CI) is 0.0000324. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.65). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV006301828: Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID:23470839);". Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I40F: Uncertain_significance (ClinVar VariationId 3343121, 2 stars)

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Consequence

ARSL
NM_000047.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 7.65

Publications

5 publications found

Variant links:

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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ARSL links:

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new If you want to explore the variant's impact on the transcript NM_000047.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 points.

Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000032, AC = 1 — absent/extremely rare (O3 moderate [+2])

Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARSL	NM_000047.3	MANE Select	c.119T>G	p.Ile40Ser	missense	Exon 3 of 11	NP_000038.2	P51690
ARSL	NM_001282628.2		c.194T>G	p.Ile65Ser	missense	Exon 4 of 12	NP_001269557.1	F5GYY5
ARSL	NM_001369080.1		c.194T>G	p.Ile65Ser	missense	Exon 4 of 12	NP_001356009.1	F5GYY5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARSL	ENST00000381134.9	TSL:1 MANE Select	c.119T>G	p.Ile40Ser	missense	Exon 3 of 11	ENSP00000370526.3	P51690
ARSL	ENST00000545496.6	TSL:2	c.194T>G	p.Ile65Ser	missense	Exon 4 of 12	ENSP00000441417.1	F5GYY5
ARSL	ENST00000672027.1		c.194T>G	p.Ile65Ser	missense	Exon 4 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183338

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.0000761

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112141

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34321

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30900

American (AMR)

AF:

0.00

AC:

AN:

10579

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3544

South Asian (SAS)

AF:

0.00

AC:

AN:

2671

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6141

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53226

Other (OTH)

AF:

0.00

AC:

AN:

1525

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

X-linked chondrodysplasia punctata 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.74

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

PhyloP100

7.7

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Varity_R

0.74

gMVP

1.0

Mutation Taster

=49/51

disease causing (ClinVar)

(source)

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

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over