X-2960404-GTCTC-GTCTCTCTC

Variant names:

• chrX-2960404-G-GTCTC
• rs200332753
• NM_000047.3:c.-8_-5dupGAGA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001369079.1(ARSL):​c.20_23dupGAGA​(p.Asp8GlufsTer70) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 20)
• Consequence: ARSL NM_001369079.1 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369079.1. 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.-8_-5dupGAGA		5_prime_UTR	Exon 2 of 11	NP_000038.2	P51690
	ARSL	NM_001369079.1		c.20_23dupGAGA	p.Asp8GlufsTer70	frameshift	Exon 2 of 11	NP_001356008.1
	ARSL	NM_001282628.2		c.-219_-216dupGAGA		5_prime_UTR	Exon 2 of 12	NP_001269557.1	F5GYY5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	ENST00000381134.9	TSL:1 MANE Select	c.-8_-5dupGAGA		5_prime_UTR	Exon 2 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.-219_-216dupGAGA		5_prime_UTR	Exon 2 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.-219_-216dupGAGA		5_prime_UTR	Exon 2 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 20

Alfa AF: 0.0000113 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3

Splicing

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

Other links and lift over

dbSNP: rs200332753; hg19: chrX-2878445;