rs34412194

chrX-2949610-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000047.3(ARSL):c.548G>A(p.Arg183His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,209,010 control chromosomes in the GnomAD database, including 46 homozygotes. There are 1,495 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R183R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., 341 hem., cov: 22)
  • Exomes 𝑓: 0.0036 (28 hom. 1154 hem.)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.67

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=0.0050126314).
• BP6: Variant X-2949610-C-T is Benign according to our data. Variant chrX-2949610-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 157734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-2949610-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1420/110837) while in subpopulation AFR AF= 0.0385 (1173/30460). AF 95% confidence interval is 0.0367. There are 18 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSL	NM_000047.3	c.548G>A	p.Arg183His	missense_variant	6/11	ENST00000381134.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSL	ENST00000381134.9	c.548G>A	p.Arg183His	missense_variant	6/11	1	NM_000047.3	P4

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1417 AN: 110783 Hom.: 18 Cov.: 22 AF XY: 0.0103 AC XY: 339 AN XY: 33005

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00502

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00426 AC: 780 AN: 183199 Hom.: 7 AF XY: 0.00324 AC XY: 219 AN XY: 67657

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.00243

GnomAD4 exome AF: 0.00364 AC: 3999 AN: 1098173 Hom.: 28 Cov.: 32 AF XY: 0.00317 AC XY: 1154 AN XY: 363529

Gnomad4 AFR exome AF: 0.0407

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.000222

Gnomad4 NFE exome AF: 0.00313

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.0128 AC: 1420 AN: 110837 Hom.: 18 Cov.: 22 AF XY: 0.0103 AC XY: 341 AN XY: 33069

Gnomad4 AFR AF: 0.0385

Gnomad4 AMR AF: 0.00501

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000168

Gnomad4 NFE AF: 0.00334

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00388 Hom.: 132

Bravo AF: 0.0141

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00312 AC: 9

ESP6500AA AF: 0.0389 AC: 149

ESP6500EA AF: 0.00297 AC: 20

ExAC AF: 0.00474 AC: 575

EpiCase AF: 0.00224

EpiControl AF: 0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2017	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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Chondrodysplasia punctata, brachytelephalangic, autosomal Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 04, 2015

- -

X-linked chondrodysplasia punctata 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2023

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.0020
Dann	Benign	0.86
DEOGEN2	Uncertain	0.46	T;.;T
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.12	T;T;T
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Uncertain	-0.052	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.030	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.019
MVP		0.86
MPC		0.55
ClinPred		0.0060	T
GERP RS		-6.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.76

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: rs34412194; hg19: chrX-2867651;