NM_000047.3:c.1694T>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000047.3(ARSL):c.1694T>G(p.Ile565Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,202,578 control chromosomes in the GnomAD database, including 3 homozygotes. There are 760 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., 47 hem., cov: 22)

Exomes 𝑓: 0.0019 ( 3 hom. 713 hem. )

Consequence

ARSL
NM_000047.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.39

Publications

1 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010291815).

BP6

Variant X-2934908-A-C is Benign according to our data. Variant chrX-2934908-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547861.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00138 (153/111028) while in subpopulation SAS AF = 0.00618 (16/2587). AF 95% confidence interval is 0.00388. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 47 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSL	NM_000047.3 link	c.1694T>G	p.Ile565Ser	missense_variant	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.1694T>G	p.Ile565Ser	missense_variant	Exon 11 of 11	1	NM_000047.3	ENSP00000370526.3		P51690

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

152

AN:

110975

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000482

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00578

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00229

Gnomad OTH

AF:

0.00134

GnomAD2 exomes

AF:

0.00144

AC:

255

AN:

177304

AF XY:

0.00156

show subpopulations

Gnomad AFR exome

AF:

0.000460

Gnomad AMR exome

AF:

0.000890

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00188

AC:

2055

AN:

1091550

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

713

AN XY:

357856

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

26333

American (AMR)

AF:

0.000657

AC:

AN:

34998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19061

East Asian (EAS)

AF:

0.00

AC:

AN:

30140

South Asian (SAS)

AF:

0.00326

AC:

174

AN:

53330

European-Finnish (FIN)

AF:

0.000174

AC:

AN:

40342

Middle Eastern (MID)

AF:

0.00114

AC:

AN:

3509

European-Non Finnish (NFE)

AF:

0.00210

AC:

1762

AN:

838077

Other (OTH)

AF:

0.00175

AC:

AN:

45760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.00138

AC:

153

AN:

111028

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

AN XY:

33248

show subpopulations

African (AFR)

AF:

0.000294

AC:

AN:

30635

American (AMR)

AF:

0.000481

AC:

AN:

10385

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3502

South Asian (SAS)

AF:

0.00618

AC:

AN:

2587

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5938

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00229

AC:

121

AN:

52940

Other (OTH)

AF:

0.00133

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00214

Hom.:

Bravo

AF:

0.00111

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00149

AC:

ExAC

AF:

0.00152

AC:

184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked chondrodysplasia punctata 1

Uncertain:1Benign:1

Jan 04, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 30, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chondrodysplasia punctata, brachytelephalangic, autosomal

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ARSE p.Ile520Ser variant was not identified in the literature but was identified in dbSNP (ID: rs142375403), ClinVar (classified as uncertain significance by Mayo Clinic and as benign by Invitae), and LOVD 3.0. The variant was identified in control databases in 283 of 199026 chromosomes (109 hemizygous) at a frequency of 0.001422 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 46 of 17733 chromosomes (freq: 0.002594), European (non-Finnish) in 201 of 89630 chromosomes (freq: 0.002243), Other in 5 of 5143 chromosomes (freq: 0.000972), Latino in 24 of 27605 chromosomes (freq: 0.000869), African in 6 of 18858 chromosomes (freq: 0.000318) and European (Finnish) in 1 of 18140 chromosomes (freq: 0.000055), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Ile520 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

0.26

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.72

D;.;D

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.76

T;T;T

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.4

.;.;L

PhyloP100

1.4

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Benign

0.20

Sift

Benign

0.046

D;D;D

Sift4G

Benign

0.077

T;T;T

Polyphen

0.35

B;B;B

Vest4

0.052

MVP

0.85

MPC

0.67

ClinPred

0.037

GERP RS

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.41

gMVP

0.85

Mutation Taster

=100/0

polymorphism (auto)

(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