chrX-2953236-G-A

Variant names:

• chrX-2953236-G-A
• rs145946864
• NM_000047.3:c.337C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000047.3(ARSL):​c.337C>T​(p.Leu113Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 112,393 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.529

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-2953236-G-A is Pathogenic according to our data. Variant chrX-2953236-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157732.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSL	NM_000047.3	c.337C>T	p.Leu113Phe	missense_variant	Exon 5 of 11	ENST00000381134.9	NP_000038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSL	ENST00000381134.9	c.337C>T	p.Leu113Phe	missense_variant	Exon 5 of 11	1	NM_000047.3	ENSP00000370526.3

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112393 Hom.: 0 Cov.: 24 AF XY: 0.0000290 AC XY: 1 AN XY: 34535

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

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183373 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67815

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112393 Hom.: 0 Cov.: 24 AF XY: 0.0000290 AC XY: 1 AN XY: 34535

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

Bravo AF: 0.0000113

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

May 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on splicing -

Nov 30, 2019

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked chondrodysplasia punctata 1 Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	11
DANN	Benign	0.13
DEOGEN2	Uncertain	0.69	D;.;D;.
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.13	.;.;N;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Benign	0.23
Sift	Benign	0.66	T;T;T;T
Sift4G	Benign	0.77	T;T;T;.
Polyphen		0.0090	B;B;B;.
Vest4		0.093
MVP		0.76
MPC		1.3
ClinPred		0.68	D
GERP RS		3.5
Varity_R		0.31
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.74		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145946864; hg19: chrX-2871277;