chrX-2934859-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PVS1_ModeratePP5_Very_StrongBS2_Supporting

The NM_000047.3(ARSL):c.1743G>A(p.Trp581*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,198,580 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000017 ( 0 hom. 6 hem. )

Consequence

ARSL
NM_000047.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 1.21

Publications

6 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ARSL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0153 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PP5

Variant X-2934859-C-T is Pathogenic according to our data. Variant chrX-2934859-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSL	NM_000047.3 link	c.1743G>A	p.Trp581*	stop_gained	Exon 11 of 11	ENST00000381134.9	NP_000038.2	P51690

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSL	ENST00000381134.9 link	c.1743G>A	p.Trp581*	stop_gained	Exon 11 of 11	1	NM_000047.3	ENSP00000370526.3		P51690

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

111127

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000566

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000568

AC:

AN:

175970

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000175

AC:

AN:

1087453

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

354405

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26237

American (AMR)

AF:

0.00

AC:

AN:

34722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19016

East Asian (EAS)

AF:

0.00

AC:

AN:

30123

South Asian (SAS)

AF:

0.00

AC:

AN:

53287

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3082

European-Non Finnish (NFE)

AF:

0.0000204

AC:

AN:

834993

Other (OTH)

AF:

0.0000438

AC:

AN:

45621

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000648), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.394

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000270

AC:

AN:

111127

Hom.:

Cov.:

AF XY:

0.0000600

AC XY:

AN XY:

33335

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30593

American (AMR)

AF:

0.00

AC:

AN:

10407

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.00

AC:

AN:

3529

South Asian (SAS)

AF:

0.00

AC:

AN:

2600

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5953

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000566

AC:

AN:

52990

Other (OTH)

AF:

0.00

AC:

AN:

1492

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked chondrodysplasia punctata 1

Pathogenic:9Other:1

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 07, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PVS1_MOD, PS4, PM2_SUP -

May 23, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2, PP5-The variant is expected to result in an absent or disrupted protein product. Low frequency in gnomAD population databases. It has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 11529). It has been previously reported as causative for chondrodysplasia punctata (PMID: 9863597, 12567415) -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 30, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 18, 2023

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PVS1 moderate, PS4 strong, PM2 supporting, PP1 supporting -

May 30, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Apr 30, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1743G>A (p.W581*) alteration, located in exon 11 (coding exon 10) of the ARSL gene, consists of a G to A substitution at nucleotide position 1743. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 581. This alteration occurs at the 3' terminus of the ARSL gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 1.5% of the protein. The exact functional effect of this alteration is unknown. Based on data from gnomAD, the c.1743G>A allele has an overall frequency of 0.001% (2/197636) total alleles studied, with 1 hemizygote observed. The highest observed frequency was 0.002% (2/89531) of European (non-Finnish) alleles. This variant was reported in multiple individuals with features consistent with ARSL-related chondrodysplasia punctata (Sheffield, 1998; Brunetti-Pierri, 2003; Mazzone, 2019; Bertoli-Avella, 2021). Based on the available evidence, this alteration is classified as pathogenic. -

See cases

Pathogenic:1

Feb 18, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. -

Chondrodysplasia punctata, brachytelephalangic, autosomal

Pathogenic:1

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Trp581*) in the ARSE gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the ARSE protein. This variant is present in population databases (rs80338714, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with chondrodysplasia punctata (PMID: 9863597, 12567415). ClinVar contains an entry for this variant (Variation ID: 11529). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Jul 31, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation as the last 9 amino acid(s) are lost; This variant is associated with the following publications: (PMID: 9863597, 34529350, 32860008, 19839041, 30084160, 12567415, 26526591) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Benign

0.93

FATHMM_MKL

Benign

0.75

PhyloP100

1.2

Vest4

0.40

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=4/196

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over