NM_000047.3:c.786G>A

Variant names:

• chrX-2949372-C-T
• rs17325750
• NM_000047.3:c.786G>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.786G>A​(p.Thr262Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0729 in 1,208,970 control chromosomes in the GnomAD database, including 2,596 homozygotes. There are 28,239 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (186 hom., 1899 hem., cov: 22)
  • Exomes 𝑓: 0.074 (2410 hom. 26340 hem.)
• Consequence: ARSL NM_000047.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.83
• Publications: 3 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=-0.8).
• BP6: Variant X-2949372-C-T is Benign according to our data. Variant chrX-2949372-C-T is described in ClinVar as Benign. ClinVar VariationId is 157736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0922 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	NM_000047.3	MANE Select	c.786G>A	p.Thr262Thr	synonymous	Exon 6 of 11	NP_000038.2
	ARSL	NM_001282628.2		c.861G>A	p.Thr287Thr	synonymous	Exon 7 of 12	NP_001269557.1
	ARSL	NM_001369080.1		c.861G>A	p.Thr287Thr	synonymous	Exon 7 of 12	NP_001356009.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	ENST00000381134.9	TSL:1 MANE Select	c.786G>A	p.Thr262Thr	synonymous	Exon 6 of 11	ENSP00000370526.3
	ARSL	ENST00000545496.6	TSL:2	c.861G>A	p.Thr287Thr	synonymous	Exon 7 of 12	ENSP00000441417.1
	ARSL	ENST00000672027.1		c.861G>A	p.Thr287Thr	synonymous	Exon 7 of 12	ENSP00000500220.1

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 6530 AN: 110786 Hom.: 187 Cov.: 22

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0659

Gnomad AMR AF: 0.0974

Gnomad ASJ AF: 0.0774

Gnomad EAS AF: 0.000565

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.0718

Gnomad MID AF: 0.0750

Gnomad NFE AF: 0.0822

Gnomad OTH AF: 0.0533

GnomAD2 exomes AF: 0.0784 AC: 14357 AN: 183226 AF XY: 0.0709

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.0749

Gnomad EAS exome AF: 0.0000721

Gnomad FIN exome AF: 0.0725

Gnomad NFE exome AF: 0.0814

Gnomad OTH exome AF: 0.0770

GnomAD4 exome AF: 0.0744 AC: 81648 AN: 1098133 Hom.: 2410 Cov.: 32 AF XY: 0.0725 AC XY: 26340 AN XY: 363491

African (AFR) AF: 0.00864 AC: 228 AN: 26402

American (AMR) AF: 0.171 AC: 6017 AN: 35171

Ashkenazi Jewish (ASJ) AF: 0.0780 AC: 1512 AN: 19385

East Asian (EAS) AF: 0.000199 AC: 6 AN: 30206

South Asian (SAS) AF: 0.0319 AC: 1726 AN: 54149

European-Finnish (FIN) AF: 0.0752 AC: 3049 AN: 40531

Middle Eastern (MID) AF: 0.0387 AC: 160 AN: 4135

European-Non Finnish (NFE) AF: 0.0783 AC: 65973 AN: 842057

Other (OTH) AF: 0.0646 AC: 2977 AN: 46097

GnomAD4 genome AF: 0.0588 AC: 6522 AN: 110837 Hom.: 186 Cov.: 22 AF XY: 0.0574 AC XY: 1899 AN XY: 33077

African (AFR) AF: 0.0108 AC: 331 AN: 30572

American (AMR) AF: 0.0972 AC: 1002 AN: 10313

Ashkenazi Jewish (ASJ) AF: 0.0774 AC: 204 AN: 2637

East Asian (EAS) AF: 0.000567 AC: 2 AN: 3530

South Asian (SAS) AF: 0.0285 AC: 74 AN: 2593

European-Finnish (FIN) AF: 0.0718 AC: 420 AN: 5846

Middle Eastern (MID) AF: 0.0685 AC: 15 AN: 219

European-Non Finnish (NFE) AF: 0.0822 AC: 4350 AN: 52944

Other (OTH) AF: 0.0527 AC: 79 AN: 1500

Alfa AF: 0.0776 Hom.: 1970

Bravo AF: 0.0624

EpiCase AF: 0.0790

EpiControl AF: 0.0783

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Chondrodysplasia punctata, brachytelephalangic, autosomal (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.037
DANN	Benign	0.49
PhyloP100		-1.8
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: rs17325750; hg19: chrX-2867413; COSMIC: COSV66966083; COSMIC: COSV66966083;