X-2953163-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM5PP3_StrongPP5BS2

The NM_000047.3(ARSL):c.410G>C(p.Gly137Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000156 in 1,208,664 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., 6 hem., cov: 24)

Exomes 𝑓: 0.00015 ( 0 hom. 60 hem. )

Consequence

ARSL
NM_000047.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3O:1

Conservation

PhyloP100: 4.61

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 Uncertain_significance. Variant got 3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-2953163-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11525.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant X-2953163-C-G is Pathogenic according to our data. Variant chrX-2953163-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21033.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, not_provided=1, Likely_pathogenic=4}. Variant chrX-2953163-C-G is described in Lovd as [Pathogenic].

BS2

High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSL	NM_000047.3 linkuse as main transcript	c.410G>C	p.Gly137Ala	missense_variant	5/11	ENST00000381134.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSL	ENST00000381134.9 linkuse as main transcript	c.410G>C	p.Gly137Ala	missense_variant	5/11	1	NM_000047.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

112469

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

AN XY:

34625

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000945

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000337

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

183389

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

67831

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000627

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

168

AN:

1096195

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

AN XY:

361667

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.000124

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000178

AC:

AN:

112469

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

AN XY:

34625

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000945

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000162

Gnomad4 NFE

AF:

0.000337

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Chondrodysplasia punctata, brachytelephalangic, autosomal

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 18, 2022	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 137 of the ARSE protein (p.Gly137Ala). This variant is present in population databases (rs80338711, gnomAD 0.02%). This missense change has been observed in individuals with X-linked chondrodysplasia punctata (PMID: 9863597, 18348268). ClinVar contains an entry for this variant (Variation ID: 21033). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ARSE function (PMID: 23470839). This variant disrupts the p.Gly137 amino acid residue in ARSE. Other variant(s) that disrupt this residue have been observed in individuals with ARSE-related conditions (PMID: 7720070), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2024	Variant summary: ARSL c.410G>C (p.Gly137Ala) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 205545 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ARSL causing Chondrodysplasia Punctata 1, X-Linked Recessive (0.00013 vs ND), allowing no conclusion about variant significance. c.410G>C has been reported in the literature in individuals affected with Chondrodysplasia Punctata 1, X-Linked Recessive. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity. ClinVar contains an entry for this variant (Variation ID: 21033). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

X-linked chondrodysplasia punctata 1

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine (exon 5). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 10 hemizygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 hemizygotes, 0 homozygotes). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternative missense change at the same residue (p.Gly137Val) has been reported as pathogenic and was found in patients with chondrodysplasia punctata (ClinVar, PMID: 7720070). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been previously described as pathogenic in three hemizygous patients with chondrodysplasia punctata (ClinVar, PMID: 23470839, PMID: 18348268, PMID: 9863597). The variant was confirmed to be inherited from asymptomatic, heterozygous mothers in all three cases. This variant has also been described as a VUS, in a primary care cohort of unknown phenotype (PMID: 29565423). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional analysis of transfected COS-7 cells found mutant protein had negligible enzyme activity (PMID: 23470839) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Coffin-Siris syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 27, 2024

Variant summary: ARID1B c.410G>C (p.Gly137Ala) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 137314 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.410G>C in individuals affected with Coffin-Siris Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 20, 2022

Identified in unrelated male patients with clinical features of chondrodysplasia punctata; however, in one family, the variant was also identified in a clinically unaffected mother and maternal grandfather, suggesting possible reduced penetrance of this variant (Nino et al., 2008; Sheffield et al., 1998); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate reduced ARSE activity (Matos-Miranda et al., 2013); This variant is associated with the following publications: (PMID: 7720070, 24645908, 24033266, 28654958, 34426522, 18348268, 23470839, 9863597, 34697415) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 08, 2013

The Gly137Ala variant in ARSE has been previously identified in 2 males with chondrodysplasia punctata; however, this variant was also identified in one unaffected male family member (Sheffield 1998, Nino 2008). Variants in a paralogous gene (ARSB) at the same position have also been identified in an individual with Maroteux-Lamy syndrome, which also features skeletal abnormalities (Franco 1995). Functional studies indicate that the Gly137Ala variant leads to reduced ARSE activity (Matos-Miranda 2013). In summary, although some data support a disease-causing role, there is currently insufficient evidence for pathogenicity leading to a current classification of uncertain significance. -

ARSL-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 15, 2024

The ARSL c.410G>C variant is predicted to result in the amino acid substitution p.Gly137Ala. This variant has been previously reported in individuals with mild or a suspected diagnosis of chondrodysplasia punctata (Sheffield et al. 1998. PubMed ID: 9863597; Nino et al. 2008. PubMed ID: 18348268). In one study the variant was also found in proband's asymptomatic maternal grandfather and his carrier mother (Sheffield et al. 1998. PubMed ID: 9863597), which can be suggestive of reduced penetrance. In vitro functional studies found that over a specific time course this variant had negligible activity compared to wild type allele (Matos-Miranda et al. 2013. PubMed ID: 23470839). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including ten hemizygous alleles. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.75

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;D;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.9

D;D;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;.

Polyphen

1.0

D;D;D;.

Vest4

0.92

MVP

0.96

MPC

1.3

ClinPred

0.94

GERP RS

3.5

Varity_R

0.81

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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