rs142375403

Variant names:

• chrX-2934908-A-C
• rs142375403
• NM_000047.3:c.1694T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000047.3(ARSL):​c.1694T>G​(p.Ile565Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,202,578 control chromosomes in the GnomAD database, including 3 homozygotes. There are 760 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., 47 hem., cov: 22)
  • Exomes 𝑓: 0.0019 (3 hom. 713 hem.)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.39
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010291815).
• BP6: Variant X-2934908-A-C is Benign according to our data. Variant chrX-2934908-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547861.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00138 (153/111028) while in subpopulation SAS AF = 0.00618 (16/2587). AF 95% confidence interval is 0.00388. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 47 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.1694T>G	p.Ile565Ser	missense	Exon 11 of 11	NP_000038.2	P51690
	ARSL	NM_001282628.2		c.1769T>G	p.Ile590Ser	missense	Exon 12 of 12	NP_001269557.1	F5GYY5
	ARSL	NM_001369080.1		c.1769T>G	p.Ile590Ser	missense	Exon 12 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.1694T>G	p.Ile565Ser	missense	Exon 11 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.1769T>G	p.Ile590Ser	missense	Exon 12 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.1769T>G	p.Ile590Ser	missense	Exon 12 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 152 AN: 110975 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000482

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00578

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.00144 AC: 255 AN: 177304 AF XY: 0.00156

Gnomad AFR exome AF: 0.000460

Gnomad AMR exome AF: 0.000890

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00188 AC: 2055 AN: 1091550 Hom.: 3 Cov.: 29 AF XY: 0.00199 AC XY: 713 AN XY: 357856

African (AFR) AF: 0.000190 AC: 5 AN: 26333

American (AMR) AF: 0.000657 AC: 23 AN: 34998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19061

East Asian (EAS) AF: 0.00 AC: 0 AN: 30140

South Asian (SAS) AF: 0.00326 AC: 174 AN: 53330

European-Finnish (FIN) AF: 0.000174 AC: 7 AN: 40342

Middle Eastern (MID) AF: 0.00114 AC: 4 AN: 3509

European-Non Finnish (NFE) AF: 0.00210 AC: 1762 AN: 838077

Other (OTH) AF: 0.00175 AC: 80 AN: 45760

GnomAD4 genome AF: 0.00138 AC: 153 AN: 111028 Hom.: 0 Cov.: 22 AF XY: 0.00141 AC XY: 47 AN XY: 33248

African (AFR) AF: 0.000294 AC: 9 AN: 30635

American (AMR) AF: 0.000481 AC: 5 AN: 10385

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3502

South Asian (SAS) AF: 0.00618 AC: 16 AN: 2587

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00229 AC: 121 AN: 52940

Other (OTH) AF: 0.00133 AC: 2 AN: 1506

Alfa AF: 0.00214 Hom.: 19

Bravo AF: 0.00111

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00149 AC: 10

ExAC AF: 0.00152 AC: 184

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.4
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.20
Sift	Benign	0.046	D
Sift4G	Benign	0.077	T
Polyphen		0.35	B
Vest4		0.052
MVP		0.85
MPC		0.67
ClinPred		0.037	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.85
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: rs142375403; hg19: chrX-2852949;