X-2907438-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001669.4(ARSD):​c.1615G>T​(p.Ala539Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000888 in 112,605 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: ARSD NM_001669.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11247656).

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>T	p.Ala539Ser	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>T	p.Ala539Ser	missense	Exon 10 of 10	ENSP00000370546.1	P51689-1
	ARSD	ENST00000954947.1		c.1480G>T	p.Ala494Ser	missense	Exon 9 of 9	ENSP00000625006.1
	ARSD	ENST00000954948.1		c.1180G>T	p.Ala394Ser	missense	Exon 7 of 7	ENSP00000625007.1

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112605 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000322

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112605 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34755

African (AFR) AF: 0.0000322 AC: 1 AN: 31043

American (AMR) AF: 0.00 AC: 0 AN: 10705

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2717

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53283

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.4
DANN	Benign	0.68
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.080	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.36
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.11
Sift	Benign	0.59	T
Sift4G	Benign	0.64	T
Polyphen		0.043	B
Vest4		0.016
MutPred		0.35		Gain of disorder (P = 0.0306)
MVP		0.72
MPC		0.14
ClinPred		0.048	T
GERP RS		-5.0
Varity_R		0.11
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;