X-2960404-GTCTC-GTC

Variant names:

• chrX-2960404-GTC-G
• rs200332753
• NM_000047.3:c.-6_-5delGA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_001369079.1(ARSL):​c.22_23delGA​(p.Asp8GlnfsTer68) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,192,194 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 177 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 8 hem., cov: 20)
  • Exomes 𝑓: 0.00032 (0 hom. 169 hem.)
• Consequence: ARSL NM_001369079.1 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.355
• 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: Benign. The variant received -8 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 39 pathogenic variants in the truncated region.
• BP6: Variant X-2960404-GTC-G is Benign according to our data. Variant chrX-2960404-GTC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1702383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000247 (27/109111) while in subpopulation SAS AF = 0.00572 (14/2446). AF 95% confidence interval is 0.00346. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

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.-6_-5delGA		5_prime_UTR	Exon 2 of 11	NP_000038.2	P51690
	ARSL	NM_001369079.1		c.22_23delGA	p.Asp8GlnfsTer68	frameshift	Exon 2 of 11	NP_001356008.1
	ARSL	NM_001282628.2		c.-217_-216delGA		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.-6_-5delGA		5_prime_UTR	Exon 2 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.-217_-216delGA		5_prime_UTR	Exon 2 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.-217_-216delGA		5_prime_UTR	Exon 2 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes AF: 0.000248 AC: 27 AN: 109071 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000569

Gnomad SAS AF: 0.00570

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.0000763

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000601 AC: 109 AN: 181507 AF XY: 0.000860

Gnomad AFR exome AF: 0.0000764

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.000651

Gnomad FIN exome AF: 0.0000669

Gnomad NFE exome AF: 0.0000857

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000319 AC: 345 AN: 1083083 Hom.: 0 AF XY: 0.000481 AC XY: 169 AN XY: 351231

African (AFR) AF: 0.00 AC: 0 AN: 26119

American (AMR) AF: 0.00 AC: 0 AN: 34975

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 40 AN: 19061

East Asian (EAS) AF: 0.000168 AC: 5 AN: 29796

South Asian (SAS) AF: 0.00407 AC: 219 AN: 53775

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38837

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4079

European-Non Finnish (NFE) AF: 0.0000722 AC: 60 AN: 831015

Other (OTH) AF: 0.000440 AC: 20 AN: 45426

GnomAD4 genome AF: 0.000247 AC: 27 AN: 109111 Hom.: 0 Cov.: 20 AF XY: 0.000253 AC XY: 8 AN XY: 31635

African (AFR) AF: 0.0000994 AC: 3 AN: 30167

American (AMR) AF: 0.00 AC: 0 AN: 10130

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 3 AN: 2612

East Asian (EAS) AF: 0.000571 AC: 2 AN: 3501

South Asian (SAS) AF: 0.00572 AC: 14 AN: 2446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5471

Middle Eastern (MID) AF: 0.00465 AC: 1 AN: 215

European-Non Finnish (NFE) AF: 0.0000763 AC: 4 AN: 52416

Other (OTH) AF: 0.00 AC: 0 AN: 1475

Alfa AF: 0.000113 Hom.: 4

Bravo AF: 0.000144

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ARSL-related disorder (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.35
Mutation Taster		=192/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs200332753; hg19: chrX-2878445;