rs200785812

Variant names:

• chrX-2907438-C-T
• rs200785812
• NM_001669.4:c.1615G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-2907438-C-T
• chrX-2907438-C-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001669.4(ARSD):​c.1615G>A​(p.Ala539Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000686 in 1,210,166 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A539D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.000068 (0 hom. 28 hem.)
• Consequence: ARSD NM_001669.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 0.359
• Publications: 2 publications found

Genes affected

ARSD (HGNC:717): (arylsulfatase D) The protein encoded by this gene is a member of the sulfatase family. Sulfatases are essential for the correct composition of bone and cartilage matrix. The encoded protein is postranslationally glycosylated and localized to the lysosome. This gene is located within a cluster of similar arylsulfatase genes on chromosome X. A related pseudogene has been identified in the pseudoautosomal region of chromosome Y. [provided by RefSeq, Jul 2011]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013090938).
• BS2: High Hemizygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001669.4. 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
	ARSD	NM_001669.4	MANE Select	c.1615G>A	p.Ala539Thr	missense	Exon 10 of 10	NP_001660.2	P51689-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSD	ENST00000381154.6	TSL:1 MANE Select	c.1615G>A	p.Ala539Thr	missense	Exon 10 of 10	ENSP00000370546.1	P51689-1
	ARSD	ENST00000954947.1		c.1480G>A	p.Ala494Thr	missense	Exon 9 of 9	ENSP00000625006.1
	ARSD	ENST00000954948.1		c.1180G>A	p.Ala394Thr	missense	Exon 7 of 7	ENSP00000625007.1

Frequencies

GnomAD3 genomes AF: 0.0000710 AC: 8 AN: 112604 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00197

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000145 AC: 26 AN: 179373 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00182

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000683 AC: 75 AN: 1097511 Hom.: 0 Cov.: 31 AF XY: 0.0000772 AC XY: 28 AN XY: 362911

African (AFR) AF: 0.0000379 AC: 1 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19366

East Asian (EAS) AF: 0.00152 AC: 46 AN: 30185

South Asian (SAS) AF: 0.000352 AC: 19 AN: 53946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40461

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841817

Other (OTH) AF: 0.000130 AC: 6 AN: 46066

GnomAD4 genome AF: 0.0000710 AC: 8 AN: 112655 Hom.: 0 Cov.: 24 AF XY: 0.000115 AC XY: 4 AN XY: 34815

African (AFR) AF: 0.00 AC: 0 AN: 31111

American (AMR) AF: 0.00 AC: 0 AN: 10717

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

East Asian (EAS) AF: 0.00197 AC: 7 AN: 3546

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53276

Other (OTH) AF: 0.00 AC: 0 AN: 1527

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.000157 AC: 19

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ARSD-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.2
DANN	Benign	0.82
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.071	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.80	N
PhyloP100		0.36
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.089
Sift	Benign	0.43	T
Sift4G	Benign	0.48	T
Polyphen		0.091	B
Vest4		0.014
MVP		0.83
MPC		0.15
ClinPred		0.0079	T
GERP RS		-5.0
Varity_R		0.080
gMVP		0.33
Mutation Taster		=99/1	polymorphism

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: rs200785812; hg19: chrX-2825479; COSMIC: COSV66972987; COSMIC: COSV66972987;