X-2934973-C-T

Variant names:

• chrX-2934973-C-T
• rs753971115
• NM_000047.3:c.1629G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000047.3(ARSL):​c.1629G>A​(p.Gln543Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,209,356 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000055 (0 hom. 16 hem.)
• Consequence: ARSL NM_000047.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0750
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-2934973-C-T is Benign according to our data. Variant chrX-2934973-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1702461.
• BP7: Synonymous conserved (PhyloP=-0.075 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 16 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.1629G>A	p.Gln543Gln	synonymous	Exon 11 of 11	NP_000038.2	P51690
	ARSL	NM_001282628.2		c.1704G>A	p.Gln568Gln	synonymous	Exon 12 of 12	NP_001269557.1	F5GYY5
	ARSL	NM_001369080.1		c.1704G>A	p.Gln568Gln	synonymous	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.1629G>A	p.Gln543Gln	synonymous	Exon 11 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.1704G>A	p.Gln568Gln	synonymous	Exon 12 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.1704G>A	p.Gln568Gln	synonymous	Exon 12 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111558 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000330 AC: 6 AN: 182086 AF XY: 0.0000150

Gnomad AFR exome AF: 0.0000766

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: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 60 AN: 1097798 Hom.: 0 Cov.: 33 AF XY: 0.0000441 AC XY: 16 AN XY: 363184

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 35174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.00 AC: 0 AN: 54062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40509

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4035

European-Non Finnish (NFE) AF: 0.0000677 AC: 57 AN: 841997

Other (OTH) AF: 0.0000651 AC: 3 AN: 46065

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111558 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33716

African (AFR) AF: 0.0000326 AC: 1 AN: 30662

American (AMR) AF: 0.00 AC: 0 AN: 10438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2631

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53135

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Chondrodysplasia punctata, brachytelephalangic, autosomal (1)
-	1	-	Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.98
DANN	Benign	0.60
PhyloP100		-0.075
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs753971115; hg19: chrX-2853014;