chrX-149483072-G-C

Variant names:

• chrX-149483072-G-C
• NM_000202.8:c.1327C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000202.8(IDS):​c.1327C>G​(p.Arg443Gly) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.555

Genes affected

IDS (HGNC:5389): (iduronate 2-sulfatase) This gene encodes a member of the sulfatase family of proteins. The encoded preproprotein is proteolytically processed to generate two polypeptide chains. This enzyme is involved in the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations in this gene are associated with the X-linked lysosomal storage disease mucopolysaccharidosis type II, also known as Hunter syndrome. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

ENSG00000241489 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12781337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.1327C>G	p.Arg443Gly	missense_variant	Exon 9 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.1057C>G	p.Arg353Gly	missense_variant	Exon 9 of 9		NP_001160022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.1327C>G	p.Arg443Gly	missense_variant	Exon 9 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.694C>G	p.Arg232Gly	missense_variant	Exon 14 of 14			ENSP00000498395.1
ENSG00000241489	ENST00000422081.6	c.694C>G	p.Arg232Gly	missense_variant	Exon 9 of 9	2		ENSP00000477056.1
ENSG00000241489	ENST00000441880.1	n.*18C>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Uncertain:1

Jul 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 443 of the IDS protein (p.Arg443Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IDS-related conditions. ClinVar contains an entry for this variant (Variation ID: 2092949). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.0067	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	8.8
DANN	Benign	0.94
DEOGEN2	Benign	0.41	T;.
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.60	T;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Pathogenic	1.6	D
MutationAssessor	Benign	0.90	L;.
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.2	N;.
REVEL	Uncertain	0.39
Sift	Benign	0.42	T;.
Sift4G	Benign	0.28	T;T
Polyphen		0.0040	B;.
Vest4		0.098
MutPred		0.44		Loss of stability (P = 0.0401);.;
MVP		0.48
MPC		0.26
ClinPred		0.039	T
GERP RS		0.79
Varity_R		0.20
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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-148564603;