rs80338714

Positions:

chrX-2934859-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_000047.3(ARSL):c.1743G>A(p.Trp581Ter) 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:11O:1

Conservation

PhyloP100: 1.21

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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 0 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. Variant chrX-2934859-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSL	NM_000047.3 linkuse as main transcript	c.1743G>A	p.Trp581Ter	stop_gained	11/11	ENST00000381134.9	NP_000038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSL	ENST00000381134.9 linkuse as main transcript	c.1743G>A	p.Trp581Ter	stop_gained	11/11	1	NM_000047.3	ENSP00000370526	P4

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

111127

Hom.:

Cov.:

AF XY:

0.0000600

AC XY:

AN XY:

33335

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

GnomAD3 exomes

AF:

0.00000568

AC:

AN:

175970

Hom.:

AF XY:

0.00

AC XY:

AN XY:

61106

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000204

Gnomad4 OTH exome

AF:

0.0000438

GnomAD4 genome

AF:

0.0000270

AC:

AN:

111127

Hom.:

Cov.:

AF XY:

0.0000600

AC XY:

AN XY:

33335

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000566

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked chondrodysplasia punctata 1

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 07, 2022	Criteria applied: PVS1_MOD, PS4, PM2_SUP -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Nov 30, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 23, 2024	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) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 30, 2024

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. -

Chondrodysplasia punctata, brachytelephalangic, autosomal

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

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. -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 18, 2020

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

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2024

Nonsense variant predicted to result in protein truncation as the last 9 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; 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

DANN

Benign

0.93

FATHMM_MKL

Benign

0.75

MutationTaster

Benign

1.0

A;A;A

Vest4

0.40

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over