rs80338711

chrX-2953163-C-AchrX-2953163-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000047.3(ARSL):c.410G>T(p.Gly137Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 112,469 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137A) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.61

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-2953163-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21033.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, not_provided=1, Likely_pathogenic=4}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-2953163-C-A is Pathogenic according to our data. Variant chrX-2953163-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11525.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-2953163-C-A is described in Lovd as [Pathogenic]. Variant chrX-2953163-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSL	NM_000047.3	c.410G>T	p.Gly137Val	missense_variant	5/11	ENST00000381134.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSL	ENST00000381134.9	c.410G>T	p.Gly137Val	missense_variant	5/11	1	NM_000047.3	P4

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112469 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34625

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112469 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34625

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked chondrodysplasia punctata 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 07, 1995	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.76
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-8.9	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.94
MutPred		0.93		Loss of disorder (P = 0.0702);.;.;.;
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.92
gMVP		1.0

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: rs80338711; hg19: chrX-2871204;