X-2934870-G-A

Variant names:

• chrX-2934870-G-A
• rs28935474
• NM_000047.3:c.1732C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PP3_Strong PP5 BS2

The NM_000047.3(ARSL):​c.1732C>T​(p.Pro578Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000046 in 1,086,229 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.34
• Publications: 11 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant X-2934870-G-A is Pathogenic according to our data. Variant chrX-2934870-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11528.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 3 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.1732C>T	p.Pro578Ser	missense	Exon 11 of 11	NP_000038.2	P51690
	ARSL	NM_001282628.2		c.1807C>T	p.Pro603Ser	missense	Exon 12 of 12	NP_001269557.1	F5GYY5
	ARSL	NM_001369080.1		c.1807C>T	p.Pro603Ser	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.1732C>T	p.Pro578Ser	missense	Exon 11 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.1807C>T	p.Pro603Ser	missense	Exon 12 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.1807C>T	p.Pro603Ser	missense	Exon 12 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000569 AC: 1 AN: 175820 AF XY: 0.0000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000460 AC: 5 AN: 1086229 Hom.: 0 Cov.: 29 AF XY: 0.00000850 AC XY: 3 AN XY: 353145

African (AFR) AF: 0.00 AC: 0 AN: 26258

American (AMR) AF: 0.00 AC: 0 AN: 34792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18973

East Asian (EAS) AF: 0.00 AC: 0 AN: 30099

South Asian (SAS) AF: 0.0000940 AC: 5 AN: 53173

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3129

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833913

Other (OTH) AF: 0.00 AC: 0 AN: 45574

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	X-linked chondrodysplasia punctata 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.85		Loss of disorder (P = 0.1053)
MVP		0.97
MPC		1.3
ClinPred		0.90	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.85
Mutation Taster		=71/29	disease causing (ClinVar)

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: rs28935474; hg19: chrX-2852911;