rs61733256

chrX-2958302-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000047.3(ARSL):c.157A>G(p.Ile53Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,210,149 control chromosomes in the GnomAD database, including 201 homozygotes. There are 1,810 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (95 hom., 820 hem., cov: 23)
  • Exomes 𝑓: 0.0033 (106 hom. 990 hem.)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.30

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037781894).
• BP6: Variant X-2958302-T-C is Benign according to our data. Variant chrX-2958302-T-C is described in ClinVar as [Benign]. Clinvar id is 157729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSL	NM_000047.3	c.157A>G	p.Ile53Val	missense_variant	3/11	ENST00000381134.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSL	ENST00000381134.9	c.157A>G	p.Ile53Val	missense_variant	3/11	1	NM_000047.3	P4

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 2984 AN: 111994 Hom.: 91 Cov.: 23 AF XY: 0.0235 AC XY: 804 AN XY: 34160

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00483

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000244

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00837 AC: 1534 AN: 183171 Hom.: 38 AF XY: 0.00565 AC XY: 382 AN XY: 67615

Gnomad AFR exome AF: 0.0951

Gnomad AMR exome AF: 0.00598

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.00432

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000232

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00329 AC: 3611 AN: 1098102 Hom.: 106 Cov.: 31 AF XY: 0.00272 AC XY: 990 AN XY: 363496

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00665

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000153

Gnomad4 OTH exome AF: 0.00807

GnomAD4 genome AF: 0.0268 AC: 3008 AN: 112047 Hom.: 95 Cov.: 23 AF XY: 0.0240 AC XY: 820 AN XY: 34223

Gnomad4 AFR AF: 0.0910

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.00485

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000244

Gnomad4 OTH AF: 0.0282

Alfa AF: 0.00330 Hom.: 169

Bravo AF: 0.0326

ESP6500AA AF: 0.0988 AC: 379

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00923 AC: 1120

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2016	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. -

X-linked chondrodysplasia punctata 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Chondrodysplasia punctata, brachytelephalangic, autosomal Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	0.0010
Dann	Benign	0.23
DEOGEN2	Uncertain	0.51	D;T;.
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.53	T;T;T
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.34	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.64	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.0050
MVP		0.69
MPC		0.37
ClinPred		0.0024	T
GERP RS		-7.2
Varity_R		0.039
gMVP		0.81

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: rs61733256; hg19: chrX-2876343;