NM_000047.3:c.1189G>A

Variant names:

• chrX-2938195-C-T
• rs201424543
• NM_000047.3:c.1189G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_000047.3(ARSL):​c.1189G>A​(p.Gly397Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000404 in 1,210,715 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 168 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). Synonymous variant affecting the same amino acid position (i.e. G397G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., 17 hem., cov: 24)
  • Exomes 𝑓: 0.00040 (0 hom. 151 hem.)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:4
• Conservation: PhyloP100: 6.54
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4184788).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000462 (52/112675) while in subpopulation NFE AF = 0.0006 (32/53292). AF 95% confidence interval is 0.000437. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 17 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.1189G>A	p.Gly397Arg	missense	Exon 9 of 11	NP_000038.2	P51690
	ARSL	NM_001282628.2		c.1264G>A	p.Gly422Arg	missense	Exon 10 of 12	NP_001269557.1	F5GYY5
	ARSL	NM_001369080.1		c.1264G>A	p.Gly422Arg	missense	Exon 10 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.1189G>A	p.Gly397Arg	missense	Exon 9 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.1264G>A	p.Gly422Arg	missense	Exon 10 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.1264G>A	p.Gly422Arg	missense	Exon 10 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes AF: 0.000462 AC: 52 AN: 112675 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000645

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: 0.00287

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000600

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000538 AC: 98 AN: 182070 AF XY: 0.000491

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: 0.00275

Gnomad NFE exome AF: 0.000654

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000398 AC: 437 AN: 1098040 Hom.: 0 Cov.: 34 AF XY: 0.000415 AC XY: 151 AN XY: 363472

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00222 AC: 90 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4032

European-Non Finnish (NFE) AF: 0.000393 AC: 331 AN: 842120

Other (OTH) AF: 0.000347 AC: 16 AN: 46075

GnomAD4 genome AF: 0.000462 AC: 52 AN: 112675 Hom.: 0 Cov.: 24 AF XY: 0.000488 AC XY: 17 AN XY: 34815

African (AFR) AF: 0.0000645 AC: 2 AN: 31025

American (AMR) AF: 0.00 AC: 0 AN: 10691

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2748

European-Finnish (FIN) AF: 0.00287 AC: 18 AN: 6264

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

European-Non Finnish (NFE) AF: 0.000600 AC: 32 AN: 53292

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.000354 Hom.: 1

Bravo AF: 0.000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000744 AC: 5

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.000273

EpiControl AF: 0.000415

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)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
1	-	-	X-linked chondrodysplasia punctata 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.42	T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.6	L
PhyloP100		6.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.82
Sift	Benign	0.23	T
Sift4G	Benign	0.20	T
Polyphen		0.98	D
Vest4		0.66
MutPred		0.66		Gain of MoRF binding (P = 0.0111)
MVP		0.96
MPC		1.4
ClinPred		0.82	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.81
Mutation Taster		=92/8	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: rs201424543; hg19: chrX-2856236; COSMIC: COSV66965415;