X-2934908-A-C

Position:

• chrX-2934908-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000047.3(ARSL):​c.1694T>G​(p.Ile565Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,202,578 control chromosomes in the GnomAD database, including 3 homozygotes. There are 760 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., 47 hem., cov: 22)
  • Exomes 𝑓: 0.0019 (3 hom. 713 hem.)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.39

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010291815).
• BP6: Variant X-2934908-A-C is Benign according to our data. Variant chrX-2934908-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547861.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chrX-2934908-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00138 (153/111028) while in subpopulation SAS AF= 0.00618 (16/2587). AF 95% confidence interval is 0.00388. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 47 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSL	NM_000047.3	c.1694T>G	p.Ile565Ser	missense_variant	11/11	ENST00000381134.9	NP_000038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSL	ENST00000381134.9	c.1694T>G	p.Ile565Ser	missense_variant	11/11	1	NM_000047.3	ENSP00000370526.3

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 152 AN: 110975 Hom.: 0 Cov.: 22 AF XY: 0.00139 AC XY: 46 AN XY: 33185

Gnomad AFR AF: 0.000294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000482

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00578

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00134

GnomAD3 exomes AF: 0.00144 AC: 255 AN: 177304 Hom.: 0 AF XY: 0.00156 AC XY: 97 AN XY: 62344

Gnomad AFR exome AF: 0.000460

Gnomad AMR exome AF: 0.000890

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00259

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00188 AC: 2055 AN: 1091550 Hom.: 3 Cov.: 29 AF XY: 0.00199 AC XY: 713 AN XY: 357856

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000657

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00326

Gnomad4 FIN exome AF: 0.000174

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00175

GnomAD4 genome AF: 0.00138 AC: 153 AN: 111028 Hom.: 0 Cov.: 22 AF XY: 0.00141 AC XY: 47 AN XY: 33248

Gnomad4 AFR AF: 0.000294

Gnomad4 AMR AF: 0.000481

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00618

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00133

Alfa AF: 0.00214 Hom.: 19

Bravo AF: 0.00111

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00149 AC: 10

ExAC AF: 0.00152 AC: 184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked chondrodysplasia punctata 1 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 30, 2016	- -

Chondrodysplasia punctata, brachytelephalangic, autosomal Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ARSE p.Ile520Ser variant was not identified in the literature but was identified in dbSNP (ID: rs142375403), ClinVar (classified as uncertain significance by Mayo Clinic and as benign by Invitae), and LOVD 3.0. The variant was identified in control databases in 283 of 199026 chromosomes (109 hemizygous) at a frequency of 0.001422 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 46 of 17733 chromosomes (freq: 0.002594), European (non-Finnish) in 201 of 89630 chromosomes (freq: 0.002243), Other in 5 of 5143 chromosomes (freq: 0.000972), Latino in 24 of 27605 chromosomes (freq: 0.000869), African in 6 of 18858 chromosomes (freq: 0.000318) and European (Finnish) in 1 of 18140 chromosomes (freq: 0.000055), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Ile520 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.72	D;.;D
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.4	.;.;L
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.20
Sift	Benign	0.046	D;D;D
Sift4G	Benign	0.077	T;T;T
Polyphen		0.35	B;B;B
Vest4		0.052
MVP		0.85
MPC		0.67
ClinPred		0.037	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.85

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: rs142375403; hg19: chrX-2852949;