X-2907471-G-T

Variant names:

• chrX-2907471-G-T
• rs747115406
• NM_001669.4:c.1582C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001669.4(ARSD):​c.1582C>A​(p.Pro528Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,094,858 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic 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. P528S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ARSD NM_001669.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.56
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

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.1582C>A	p.Pro528Thr	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.1582C>A	p.Pro528Thr	missense	Exon 10 of 10	ENSP00000370546.1	P51689-1
	ARSD	ENST00000954947.1		c.1447C>A	p.Pro483Thr	missense	Exon 9 of 9	ENSP00000625006.1
	ARSD	ENST00000954948.1		c.1147C>A	p.Pro383Thr	missense	Exon 7 of 7	ENSP00000625007.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1094858 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360486

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26355

American (AMR) AF: 0.00 AC: 0 AN: 34844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19271

East Asian (EAS) AF: 0.00 AC: 0 AN: 30103

South Asian (SAS) AF: 0.00 AC: 0 AN: 53439

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40217

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840543

Other (OTH) AF: 0.00 AC: 0 AN: 45959

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.022	D
Polyphen		0.14	B
Vest4		0.25
MutPred		0.51		Gain of phosphorylation at P528 (P = 0.0191)
MVP		0.93
MPC		0.27
ClinPred		0.94	D
GERP RS		3.0
Varity_R		0.51
gMVP		0.78
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs747115406; hg19: chrX-2825512;