X-2907455-G-C

Variant names:

• chrX-2907455-G-C
• NM_001669.4:c.1598C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001669.4(ARSD):​c.1598C>G​(p.Ser533Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ARSD NM_001669.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34944838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSD	NM_001669.4	c.1598C>G	p.Ser533Cys	missense_variant	Exon 10 of 10	ENST00000381154.6	NP_001660.2
ARSD	XM_005274514.3	c.1463C>G	p.Ser488Cys	missense_variant	Exon 9 of 9		XP_005274571.1
ARSD	XM_047442108.1	c.1460C>G	p.Ser487Cys	missense_variant	Exon 10 of 10		XP_047298064.1
ARSD	XM_005274515.3	c.*522C>G		3_prime_UTR_variant	Exon 10 of 10		XP_005274572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSD	ENST00000381154.6	c.1598C>G	p.Ser533Cys	missense_variant	Exon 10 of 10	1	NM_001669.4	ENSP00000370546.1
ARSD	ENST00000458014.1	c.404C>G	p.Ser135Cys	missense_variant	Exon 3 of 4	3		ENSP00000409180.1
ARSD	ENST00000495294.1	n.733C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1598C>G (p.S533C) alteration is located in exon 10 (coding exon 10) of the ARSD gene. This alteration results from a C to G substitution at nucleotide position 1598, causing the serine (S) at amino acid position 533 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	D;.
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.99	D;.
Vest4		0.17
MutPred		0.31		Loss of glycosylation at S533 (P = 0.0151);.;
MVP		0.94
MPC		0.42
ClinPred		0.72	D
GERP RS		2.1
Varity_R		0.65
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-2825496;