X-2938114-C-T

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.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. 12/19 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:7
• Conservation: PhyloP100: 2.69

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=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 id is 157728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-2938114-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSL	NM_000047.3	c.1270G>A	p.Gly424Ser	missense_variant	9/11	ENST00000381134.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSL	ENST00000381134.9	c.1270G>A	p.Gly424Ser	missense_variant	9/11	1	NM_000047.3	P4

Frequencies

GnomAD3 genomes AF: 0.526 AC: 58222 AN: 110700 Hom.: 12959 Cov.: 23 AF XY: 0.528 AC XY: 17390 AN XY: 32924

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

GnomAD3 exomes AF: 0.658 AC: 119558 AN: 181573 Hom.: 25425 AF XY: 0.684 AC XY: 45870 AN XY: 67035

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 SAS exome AF: 0.829

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

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.589

Gnomad4 ASJ exome AF: 0.747

Gnomad4 EAS exome AF: 0.861

Gnomad4 SAS exome AF: 0.824

Gnomad4 FIN exome AF: 0.626

Gnomad4 NFE exome AF: 0.664

Gnomad4 OTH exome AF: 0.652

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

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.533

Gnomad4 ASJ AF: 0.739

Gnomad4 EAS AF: 0.878

Gnomad4 SAS AF: 0.822

Gnomad4 FIN AF: 0.614

Gnomad4 NFE AF: 0.673

Gnomad4 OTH AF: 0.552

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 19, 2015	- -

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.65	T;T;T
MetaRNN	Benign	0.0000013	T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.00089	P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.94	P;P;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

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