rs5982618

Positions:

• chrX-2949609-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000047.3(ARSL):​c.549C>T​(p.Arg183=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,209,080 control chromosomes in the GnomAD database, including 268 homozygotes. There are 2,230 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (136 hom., 878 hem., cov: 22)
  • Exomes 𝑓: 0.0044 (132 hom. 1352 hem.)
• Consequence: ARSL NM_000047.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.07

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-2949609-G-A is Benign according to our data. Variant chrX-2949609-G-A is described in ClinVar as [Benign]. Clinvar id is 157735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSL	NM_000047.3	c.549C>T	p.Arg183=	synonymous_variant	6/11	ENST00000381134.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSL	ENST00000381134.9	c.549C>T	p.Arg183=	synonymous_variant	6/11	1	NM_000047.3	P4

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 3436 AN: 110827 Hom.: 134 Cov.: 22 AF XY: 0.0263 AC XY: 870 AN XY: 33027

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00453

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.0324

GnomAD3 exomes AF: 0.0102 AC: 1861 AN: 183238 Hom.: 71 AF XY: 0.00623 AC XY: 422 AN XY: 67696

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00898

Gnomad ASJ exome AF: 0.00441

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000473

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00445 AC: 4882 AN: 1098200 Hom.: 132 Cov.: 32 AF XY: 0.00372 AC XY: 1352 AN XY: 363556

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.00438

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.0311 AC: 3453 AN: 110880 Hom.: 136 Cov.: 22 AF XY: 0.0265 AC XY: 878 AN XY: 33090

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0166

Gnomad4 ASJ AF: 0.00453

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00124

Gnomad4 OTH AF: 0.0320

Alfa AF: 0.0173 Hom.: 156

Bravo AF: 0.0366

EpiCase AF: 0.00202

EpiControl AF: 0.00285

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Chondrodysplasia punctata, brachytelephalangic, autosomal Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

X-linked chondrodysplasia punctata 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs5982618; hg19: chrX-2867650;