X-2953241-C-T

Position:

• chrX-2953241-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The ENST00000381134.9(ARSL):​c.332G>A​(p.Arg111His) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 112,326 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R111P) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: ARSL ENST00000381134.9 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.80

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 7 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-2953242-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427005.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832
• PP5: Variant X-2953241-C-T is Pathogenic according to our data. Variant chrX-2953241-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372304.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSL	NM_000047.3	c.332G>A	p.Arg111His	missense_variant	5/11	ENST00000381134.9	NP_000038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSL	ENST00000381134.9	c.332G>A	p.Arg111His	missense_variant	5/11	1	NM_000047.3	ENSP00000370526	P4

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112326 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34508

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112326 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34508

Gnomad4 AFR AF: 0.00

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: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2016

The R111H variant has been published previously in association with X-linked chondrodysplasia punctata (Meyer et al., 2013). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same residue (R111P) has been reported in the Human Gene Mutation Database in association with chondrodysplasia punctata (Stenson et al., 2014). An additional missense variant (R111C) has also been observed in a patient referred to GeneDx for testing, supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.77	D;.;D;.
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.7	.;.;L;.
MutationTaster	Benign	0.89	N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.4	D;D;D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.062	T;T;T;D
Sift4G	Benign	0.072	T;T;T;.
Polyphen		1.0	D;P;D;.
Vest4		0.74
MutPred		0.61		Loss of MoRF binding (P = 0.0067);.;.;.;
MVP		0.81
MPC		1.5
ClinPred		0.90	D
GERP RS		2.6
Varity_R		0.25
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs122460153; hg19: chrX-2871282;