NM_000047.3:c.78A>G

Variant names:

• chrX-2958381-T-C
• rs35718384
• NM_000047.3:c.78A>G

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.78A>G​(p.Ala26Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,210,324 control chromosomes in the GnomAD database, including 1,167 homozygotes. There are 4,272 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A26A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.065 (565 hom., 2022 hem., cov: 23)
  • Exomes 𝑓: 0.0075 (602 hom. 2250 hem.)
• Consequence: ARSL NM_000047.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.10
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant X-2958381-T-C is Benign according to our data. Variant chrX-2958381-T-C is described in ClinVar as Benign. ClinVar VariationId is 157737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	NM_000047.3	MANE Select	c.78A>G	p.Ala26Ala	synonymous	Exon 3 of 11	NP_000038.2	P51690
	ARSL	NM_001282628.2		c.153A>G	p.Ala51Ala	synonymous	Exon 4 of 12	NP_001269557.1	F5GYY5
	ARSL	NM_001369080.1		c.153A>G	p.Ala51Ala	synonymous	Exon 4 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.78A>G	p.Ala26Ala	synonymous	Exon 3 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.153A>G	p.Ala51Ala	synonymous	Exon 4 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.153A>G	p.Ala51Ala	synonymous	Exon 4 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes AF: 0.0650 AC: 7282 AN: 112076 Hom.: 562 Cov.: 23

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00252

Gnomad SAS AF: 0.00778

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000826

Gnomad OTH AF: 0.0537

GnomAD2 exomes AF: 0.0197 AC: 3617 AN: 183210 AF XY: 0.0132

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00253

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000782

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00752 AC: 8259 AN: 1098195 Hom.: 602 Cov.: 31 AF XY: 0.00619 AC XY: 2250 AN XY: 363555

African (AFR) AF: 0.233 AC: 6153 AN: 26394

American (AMR) AF: 0.0122 AC: 429 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00156 AC: 47 AN: 30204

South Asian (SAS) AF: 0.00550 AC: 298 AN: 54136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.0133 AC: 55 AN: 4135

European-Non Finnish (NFE) AF: 0.000533 AC: 449 AN: 842130

Other (OTH) AF: 0.0180 AC: 828 AN: 46091

GnomAD4 genome AF: 0.0653 AC: 7320 AN: 112129 Hom.: 565 Cov.: 23 AF XY: 0.0589 AC XY: 2022 AN XY: 34341

African (AFR) AF: 0.223 AC: 6856 AN: 30728

American (AMR) AF: 0.0279 AC: 296 AN: 10598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00253 AC: 9 AN: 3564

South Asian (SAS) AF: 0.00781 AC: 21 AN: 2690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6195

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.000826 AC: 44 AN: 53277

Other (OTH) AF: 0.0609 AC: 93 AN: 1527

Alfa AF: 0.0265 Hom.: 311

Bravo AF: 0.0754

EpiCase AF: 0.000709

EpiControl AF: 0.00136

ClinVar

ClinVar submissions

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)
-	-	1	X-linked chondrodysplasia punctata 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.3
DANN	Benign	0.28
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs35718384; hg19: chrX-2876422;