X-2934860-C-T

Variant names:

• chrX-2934860-C-T
• rs2089174046
• NM_000047.3:c.1742G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000047.3(ARSL):​c.1742G>A​(p.Trp581*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARSL NM_000047.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.17
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• X-linked chondrodysplasia punctata 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0158 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-2934860-C-T is Pathogenic according to our data. Variant chrX-2934860-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3384622.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000047.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	NM_000047.3	MANE Select	c.1742G>A	p.Trp581*	stop_gained	Exon 11 of 11	NP_000038.2	P51690
	ARSL	NM_001282628.2		c.1817G>A	p.Trp606*	stop_gained	Exon 12 of 12	NP_001269557.1	F5GYY5
	ARSL	NM_001369080.1		c.1817G>A	p.Trp606*	stop_gained	Exon 12 of 12	NP_001356009.1	F5GYY5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	ENST00000381134.9	TSL:1 MANE Select	c.1742G>A	p.Trp581*	stop_gained	Exon 11 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.1817G>A	p.Trp606*	stop_gained	Exon 12 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.1817G>A	p.Trp606*	stop_gained	Exon 12 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	36
DANN	Benign	0.97
FATHMM_MKL	Uncertain	0.78	D
PhyloP100		2.2
Vest4		0.40
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=50/150	disease causing

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

Other links and lift over

dbSNP: rs2089174046; hg19: chrX-2852901;