X-2960404-GTCTC-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_001369079.1(ARSL):​c.20_23delGAGA​(p.Arg7ThrfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,192,476 control chromosomes in the GnomAD database, including 70 homozygotes. There are 986 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (37 hom., 427 hem., cov: 20)
  • Exomes 𝑓: 0.0019 (33 hom. 559 hem.)
• Consequence: ARSL NM_001369079.1 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.669
• 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: Orphanet, ClinGen, G2P, 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-GTCTC-G is Benign according to our data. Variant chrX-2960404-GTCTC-G is described in ClinVar as Benign. ClinVar VariationId is 254741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	NM_000047.3	MANE Select	c.-8_-5delGAGA		5_prime_UTR	Exon 2 of 11	NP_000038.2
	ARSL	NM_001369079.1		c.20_23delGAGA	p.Arg7ThrfsTer25	frameshift	Exon 2 of 11	NP_001356008.1
	ARSL	NM_001282628.2		c.-219_-216delGAGA		5_prime_UTR	Exon 2 of 12	NP_001269557.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 1723 AN: 109046 Hom.: 38 Cov.: 20

Gnomad AFR AF: 0.0538

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00652

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00142

Gnomad SAS AF: 0.00122

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000210

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00478 AC: 868 AN: 181507 AF XY: 0.00287

Gnomad AFR exome AF: 0.0555

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00188

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00190 AC: 2061 AN: 1083390 Hom.: 33 AF XY: 0.00159 AC XY: 559 AN XY: 351508

African (AFR) AF: 0.0551 AC: 1437 AN: 26092

American (AMR) AF: 0.00283 AC: 99 AN: 34976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19069

East Asian (EAS) AF: 0.00138 AC: 41 AN: 29802

South Asian (SAS) AF: 0.00147 AC: 79 AN: 53791

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38855

Middle Eastern (MID) AF: 0.00417 AC: 17 AN: 4080

European-Non Finnish (NFE) AF: 0.000218 AC: 181 AN: 831289

Other (OTH) AF: 0.00456 AC: 207 AN: 45436

GnomAD4 genome AF: 0.0158 AC: 1728 AN: 109086 Hom.: 37 Cov.: 20 AF XY: 0.0135 AC XY: 427 AN XY: 31628

African (AFR) AF: 0.0539 AC: 1625 AN: 30143

American (AMR) AF: 0.00652 AC: 66 AN: 10128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2612

East Asian (EAS) AF: 0.00143 AC: 5 AN: 3501

South Asian (SAS) AF: 0.00123 AC: 3 AN: 2446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000210 AC: 11 AN: 52416

Other (OTH) AF: 0.0122 AC: 18 AN: 1475

Alfa AF: 0.000193 Hom.: 4

Bravo AF: 0.0184

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ARSL-related disorder (1)
-	-	1	Connective tissue disorder (1)
-	-	1	not provided (1)
-	-	1	X-linked chondrodysplasia punctata 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=188/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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;