X-2953163-C-G

Variant names:

• chrX-2953163-C-G
• rs80338711
• NM_000047.3:c.410G>C
• ARSL p.Gly137Ala

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 11P and 5B. PS3 PM5 PP3_Strong PP5 BS1_Supporting BS2

The NM_000047.3(ARSL):​c.410G>C​(p.Gly137Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000156 in 1,208,664 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001766908: Published functional studies demonstrate reduced ARSL activity (PMID:23470839)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 6 hem., cov: 24)
  • Exomes 𝑓: 0.00015 (0 hom. 60 hem.)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5 O:1
• Conservation: PhyloP100: 4.61
• Publications: 13 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001766908: Published functional studies demonstrate reduced ARSL activity (PMID: 23470839); SCV005040643: "At least one publication reports experimental evidence evaluating an impact on protein function (Matos-Miranda_2013). The most pronounced variant effect results in 10%-<30% of normal activity."
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-2953163-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11525.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant X-2953163-C-G is Pathogenic according to our data. Variant chrX-2953163-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21033.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000178 (20/112469) while in subpopulation NFE AF = 0.000337 (18/53359). AF 95% confidence interval is 0.000218. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

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.410G>C	p.Gly137Ala	missense	Exon 5 of 11	NP_000038.2	P51690
	ARSL	NM_001282628.2		c.485G>C	p.Gly162Ala	missense	Exon 6 of 12	NP_001269557.1	F5GYY5
	ARSL	NM_001369080.1		c.485G>C	p.Gly162Ala	missense	Exon 6 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.410G>C	p.Gly137Ala	missense	Exon 5 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.485G>C	p.Gly162Ala	missense	Exon 6 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.485G>C	p.Gly162Ala	missense	Exon 6 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 20 AN: 112469 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000945

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000337

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 24 AN: 183389 AF XY: 0.000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000627

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 168 AN: 1096195 Hom.: 0 Cov.: 30 AF XY: 0.000166 AC XY: 60 AN XY: 361667

African (AFR) AF: 0.00 AC: 0 AN: 26356

American (AMR) AF: 0.000114 AC: 4 AN: 35142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19314

East Asian (EAS) AF: 0.00 AC: 0 AN: 30114

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54082

European-Finnish (FIN) AF: 0.000124 AC: 5 AN: 40281

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4131

European-Non Finnish (NFE) AF: 0.000177 AC: 149 AN: 840806

Other (OTH) AF: 0.000174 AC: 8 AN: 45969

GnomAD4 genome AF: 0.000178 AC: 20 AN: 112469 Hom.: 0 Cov.: 24 AF XY: 0.000173 AC XY: 6 AN XY: 34625

African (AFR) AF: 0.00 AC: 0 AN: 30943

American (AMR) AF: 0.0000945 AC: 1 AN: 10582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3610

South Asian (SAS) AF: 0.00 AC: 0 AN: 2728

European-Finnish (FIN) AF: 0.000162 AC: 1 AN: 6160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000337 AC: 18 AN: 53359

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000128

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Chondrodysplasia punctata, brachytelephalangic, autosomal (2)
-	2	-	X-linked chondrodysplasia punctata 1 (3)
-	1	-	ARSL-related disorder (1)
1	-	-	Coffin-Siris syndrome 1 (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.75
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		4.6
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.81
gMVP		0.99
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs80338711;

hg19: chrX-2871204;