X-2938114-C-T

Variant names:

• chrX-2938114-C-T
• rs35143646
• NM_000047.3:c.1270G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000047.3(ARSL):​c.1270G>A​(p.Gly424Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 110,753 control chromosomes in the GnomAD database, including 12,948 homozygotes. There are 17,389 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G424G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.53 (12948 hom., 17389 hem., cov: 23)
  • Exomes 𝑓: 0.66 (162105 hom. 244944 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.69
• Publications: 32 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2959954E-6).
• BP6: Variant X-2938114-C-T is Benign according to our data. Variant chrX-2938114-C-T is described in ClinVar as Benign. ClinVar VariationId is 157728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000047.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	NM_000047.3	MANE Select	c.1270G>A	p.Gly424Ser	missense	Exon 9 of 11	NP_000038.2
	ARSL	NM_001282628.2		c.1345G>A	p.Gly449Ser	missense	Exon 10 of 12	NP_001269557.1
	ARSL	NM_001369080.1		c.1345G>A	p.Gly449Ser	missense	Exon 10 of 12	NP_001356009.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	ENST00000381134.9	TSL:1 MANE Select	c.1270G>A	p.Gly424Ser	missense	Exon 9 of 11	ENSP00000370526.3
	ARSL	ENST00000545496.6	TSL:2	c.1345G>A	p.Gly449Ser	missense	Exon 10 of 12	ENSP00000441417.1
	ARSL	ENST00000672027.1		c.1345G>A	p.Gly449Ser	missense	Exon 10 of 12	ENSP00000500220.1

Frequencies

GnomAD3 genomes AF: 0.526 AC: 58222 AN: 110700 Hom.: 12959 Cov.: 23

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.878

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.555

GnomAD2 exomes AF: 0.658 AC: 119558 AN: 181573 AF XY: 0.684

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.595

Gnomad ASJ exome AF: 0.749

Gnomad EAS exome AF: 0.896

Gnomad FIN exome AF: 0.626

Gnomad NFE exome AF: 0.677

Gnomad OTH exome AF: 0.677

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.663 AC: 727532 AN: 1097883 Hom.: 162105 Cov.: 62 AF XY: 0.674 AC XY: 244944 AN XY: 363365

African (AFR) AF: 0.148 AC: 3900 AN: 26386

American (AMR) AF: 0.589 AC: 20732 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 14477 AN: 19376

East Asian (EAS) AF: 0.861 AC: 25994 AN: 30180

South Asian (SAS) AF: 0.824 AC: 44633 AN: 54134

European-Finnish (FIN) AF: 0.626 AC: 25350 AN: 40510

Middle Eastern (MID) AF: 0.728 AC: 2937 AN: 4032

European-Non Finnish (NFE) AF: 0.664 AC: 559470 AN: 842011

Other (OTH) AF: 0.652 AC: 30039 AN: 46063

GnomAD4 genome AF: 0.525 AC: 58193 AN: 110753 Hom.: 12948 Cov.: 23 AF XY: 0.527 AC XY: 17389 AN XY: 32987

African (AFR) AF: 0.159 AC: 4872 AN: 30632

American (AMR) AF: 0.533 AC: 5586 AN: 10471

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 1951 AN: 2640

East Asian (EAS) AF: 0.878 AC: 3043 AN: 3466

South Asian (SAS) AF: 0.822 AC: 2114 AN: 2573

European-Finnish (FIN) AF: 0.614 AC: 3584 AN: 5840

Middle Eastern (MID) AF: 0.742 AC: 155 AN: 209

European-Non Finnish (NFE) AF: 0.673 AC: 35527 AN: 52750

Other (OTH) AF: 0.552 AC: 831 AN: 1505

Alfa AF: 0.588 Hom.: 8806

Bravo AF: 0.506

TwinsUK AF: 0.659 AC: 2442

ALSPAC AF: 0.661 AC: 1909

ESP6500AA AF: 0.179 AC: 687

ESP6500EA AF: 0.671 AC: 4504

ExAC AF: 0.664 AC: 80566

EpiCase AF: 0.683

EpiControl AF: 0.686

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 19, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

X-linked chondrodysplasia punctata 1 Benign:2

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Chondrodysplasia punctata, brachytelephalangic, autosomal Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.7
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.43
Sift	Benign	0.20	T
Sift4G	Benign	0.26	T
Polyphen		0.94	P
Vest4		0.090
MPC		1.3
ClinPred		0.036	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.92
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35143646; hg19: chrX-2856155; COSMIC: COSV66965335;