chrX-2949663-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000047.3(ARSL):c.495T>C(p.His165His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,209,964 control chromosomes in the GnomAD database, including 157 homozygotes. There are 6,518 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 11 hom., 383 hem., cov: 22)

Exomes 𝑓: 0.017 ( 146 hom. 6135 hem. )

Consequence

ARSL
NM_000047.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.782

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant X-2949663-A-G is Benign according to our data. Variant chrX-2949663-A-G is described in ClinVar as Benign. ClinVar VariationId is 516293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.782 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0128 (1427/111890) while in subpopulation NFE AF = 0.0188 (1000/53169). AF 95% confidence interval is 0.0178. There are 11 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSL	NM_000047.3 link	c.495T>C	p.His165His	synonymous_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.495T>C	p.His165His	synonymous_variant	Exon 6 of 11	1	NM_000047.3	ENSP00000370526.3		P51690

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1428

AN:

111833

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00221

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.00590

Gnomad ASJ

AF:

0.0309

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00486

Gnomad FIN

AF:

0.0155

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.0134

AC:

2450

AN:

182878

AF XY:

0.0129

show subpopulations

Gnomad AFR exome

AF:

0.00213

Gnomad AMR exome

AF:

0.00358

Gnomad ASJ exome

AF:

0.0336

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.0174

Gnomad NFE exome

AF:

0.0196

Gnomad OTH exome

AF:

0.0152

GnomAD4 exome

AF:

0.0174

AC:

19149

AN:

1098074

Hom.:

146

Cov.:

AF XY:

0.0169

AC XY:

6135

AN XY:

363432

show subpopulations

African (AFR)

AF:

0.00133

AC:

AN:

26401

American (AMR)

AF:

0.00395

AC:

139

AN:

35200

Ashkenazi Jewish (ASJ)

AF:

0.0333

AC:

646

AN:

19381

East Asian (EAS)

AF:

0.0000993

AC:

AN:

30204

South Asian (SAS)

AF:

0.00623

AC:

337

AN:

54089

European-Finnish (FIN)

AF:

0.0175

AC:

710

AN:

40528

Middle Eastern (MID)

AF:

0.00484

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0196

AC:

16540

AN:

842044

Other (OTH)

AF:

0.0156

AC:

719

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

850

1700

2551

3401

4251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

634

1268

1902

2536

3170

<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:

1427

AN:

111890

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

383

AN XY:

34056

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

30837

American (AMR)

AF:

0.00589

AC:

AN:

10518

Ashkenazi Jewish (ASJ)

AF:

0.0309

AC:

AN:

2653

East Asian (EAS)

AF:

0.000282

AC:

AN:

3545

South Asian (SAS)

AF:

0.00449

AC:

AN:

2670

European-Finnish (FIN)

AF:

0.0155

AC:

AN:

6078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0188

AC:

1000

AN:

53169

Other (OTH)

AF:

0.0138

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

109

164

218

273

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:

0.0172

Hom.:

130

Bravo

AF:

0.0115

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 07, 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. -

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

X-linked chondrodysplasia punctata 1

Benign:1

Oct 23, 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

Dec 22, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.24

(source)

DANN

Benign

0.33

PhyloP100

-0.78

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