rs11055

Variant names:

• chrX-2934874-C-T
• rs11055
• NM_000047.3:c.1728G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000047.3(ARSL):​c.1728G>A​(p.Pro576Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0723 in 1,182,636 control chromosomes in the GnomAD database, including 3,011 homozygotes. There are 27,622 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (189 hom., 1689 hem., cov: 22)
  • Exomes 𝑓: 0.074 (2822 hom. 25933 hem.)
• Consequence: ARSL NM_000047.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.21
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-2934874-C-T is Benign according to our data. Variant chrX-2934874-C-T is described in ClinVar as Benign. ClinVar VariationId is 157731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0886 is higher than 0.05.

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.1728G>A	p.Pro576Pro	synonymous	Exon 11 of 11	NP_000038.2
	ARSL	NM_001282628.2		c.1803G>A	p.Pro601Pro	synonymous	Exon 12 of 12	NP_001269557.1
	ARSL	NM_001369080.1		c.1803G>A	p.Pro601Pro	synonymous	Exon 12 of 12	NP_001356009.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	ENST00000381134.9	TSL:1 MANE Select	c.1728G>A	p.Pro576Pro	synonymous	Exon 11 of 11	ENSP00000370526.3
	ARSL	ENST00000545496.6	TSL:2	c.1803G>A	p.Pro601Pro	synonymous	Exon 12 of 12	ENSP00000441417.1
	ARSL	ENST00000672027.1		c.1803G>A	p.Pro601Pro	synonymous	Exon 12 of 12	ENSP00000500220.1

Frequencies

GnomAD3 genomes AF: 0.0567 AC: 6285 AN: 110925 Hom.: 189 Cov.: 22

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0719

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00847

Gnomad FIN AF: 0.0606

Gnomad MID AF: 0.0420

Gnomad NFE AF: 0.0908

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0470 AC: 8196 AN: 174308 AF XY: 0.0372

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.0212

Gnomad ASJ exome AF: 0.0481

Gnomad EAS exome AF: 0.0000729

Gnomad FIN exome AF: 0.0626

Gnomad NFE exome AF: 0.0752

Gnomad OTH exome AF: 0.0592

GnomAD4 exome AF: 0.0739 AC: 79206 AN: 1071656 Hom.: 2822 Cov.: 29 AF XY: 0.0734 AC XY: 25933 AN XY: 353362

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0103 AC: 271 AN: 26202

American (AMR) AF: 0.0249 AC: 862 AN: 34633

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 1173 AN: 18833

East Asian (EAS) AF: 0.000200 AC: 6 AN: 30057

South Asian (SAS) AF: 0.00915 AC: 484 AN: 52894

European-Finnish (FIN) AF: 0.0698 AC: 2808 AN: 40238

Middle Eastern (MID) AF: 0.0435 AC: 136 AN: 3128

European-Non Finnish (NFE) AF: 0.0860 AC: 70528 AN: 820505

Other (OTH) AF: 0.0650 AC: 2938 AN: 45166

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0566 AC: 6283 AN: 110980 Hom.: 189 Cov.: 22 AF XY: 0.0509 AC XY: 1689 AN XY: 33184

African (AFR) AF: 0.0124 AC: 379 AN: 30652

American (AMR) AF: 0.0408 AC: 424 AN: 10403

Ashkenazi Jewish (ASJ) AF: 0.0719 AC: 189 AN: 2627

East Asian (EAS) AF: 0.00 AC: 0 AN: 3524

South Asian (SAS) AF: 0.00850 AC: 22 AN: 2588

European-Finnish (FIN) AF: 0.0606 AC: 358 AN: 5912

Middle Eastern (MID) AF: 0.0459 AC: 10 AN: 218

European-Non Finnish (NFE) AF: 0.0908 AC: 4799 AN: 52862

Other (OTH) AF: 0.0516 AC: 78 AN: 1513

Alfa AF: 0.0667 Hom.: 569

Bravo AF: 0.0529

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Chondrodysplasia punctata, brachytelephalangic, autosomal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.069
DANN	Benign	0.48
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs11055; hg19: chrX-2852915;