rs34412194

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000047.3(ARSL):c.548G>A(p.Arg183His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,209,010 control chromosomes in the GnomAD database, including 46 homozygotes. There are 1,495 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R183R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.013 ( 18 hom., 341 hem., cov: 22)

Exomes 𝑓: 0.0036 ( 28 hom. 1154 hem. )

Consequence

ARSL
NM_000047.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.67

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050126314).

BP6

Variant X-2949610-C-T is Benign according to our data. Variant chrX-2949610-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1420/110837) while in subpopulation AFR AF = 0.0385 (1173/30460). AF 95% confidence interval is 0.0367. There are 18 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSL	NM_000047.3 link	c.548G>A	p.Arg183His	missense_variant	Exon 6 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.548G>A	p.Arg183His	missense_variant	Exon 6 of 11	1	NM_000047.3	ENSP00000370526.3		P51690

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1417

AN:

110783

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0385

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00502

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000168

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.00334

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.00426

AC:

780

AN:

183199

AF XY:

0.00324

show subpopulations

Gnomad AFR exome

AF:

0.0377

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000125

Gnomad NFE exome

AF:

0.00252

Gnomad OTH exome

AF:

0.00243

GnomAD4 exome

AF:

0.00364

AC:

3999

AN:

1098173

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

1154

AN XY:

363529

show subpopulations

African (AFR)

AF:

0.0407

AC:

1074

AN:

26403

American (AMR)

AF:

0.00284

AC:

100

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54114

European-Finnish (FIN)

AF:

0.000222

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00193

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00313

AC:

2634

AN:

842108

Other (OTH)

AF:

0.00371

AC:

171

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

196

392

589

785

981

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.0128

AC:

1420

AN:

110837

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

341

AN XY:

33069

show subpopulations

African (AFR)

AF:

0.0385

AC:

1173

AN:

30460

American (AMR)

AF:

0.00501

AC:

AN:

10373

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3496

South Asian (SAS)

AF:

0.00

AC:

AN:

2551

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

5938

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00334

AC:

177

AN:

52964

Other (OTH)

AF:

0.00995

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00613

Hom.:

256

Bravo

AF:

0.0141

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00312

AC:

ESP6500AA

AF:

0.0389

AC:

149

ESP6500EA

AF:

0.00297

AC:

ExAC

AF:

0.00474

AC:

575

EpiCase

AF:

0.00224

EpiControl

AF:

0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 13, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 04, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chondrodysplasia punctata, brachytelephalangic, autosomal

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked chondrodysplasia punctata 1

Benign:1

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Jan 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.0020

(source)

DANN

Benign

0.86

DEOGEN2

Uncertain

0.46

T;.;T

FATHMM_MKL

Benign

0.0049

LIST_S2

Benign

0.12

T;T;T

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Uncertain

-0.052

MutationAssessor

Benign

-0.38

.;.;N

PhyloP100

-1.7

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.030

N;N;N

REVEL

Benign

0.25

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.019

MVP

0.86

MPC

0.55

ClinPred

0.0060

GERP RS

-6.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

gMVP

0.76

Mutation Taster

=99/1

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