chrX-149482778-C-A

Position:

• chrX-149482778-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000202.8(IDS):​c.1621G>T​(p.Gly541Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 111,934 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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 2 ACMG points.

• PM1: In a chain Iduronate 2-sulfatase 14 kDa chain (size 94) in uniprot entity IDS_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000202.8
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1992696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDS	NM_000202.8	c.1621G>T	p.Gly541Cys	missense_variant	9/9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.1351G>T	p.Gly451Cys	missense_variant	9/9		NP_001160022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.1621G>T	p.Gly541Cys	missense_variant	9/9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.988G>T	p.Gly330Cys	missense_variant	14/14			ENSP00000498395.1
ENSG00000241489	ENST00000422081.6	c.988G>T	p.Gly330Cys	missense_variant	9/9	2		ENSP00000477056.1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111934 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34094

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111934 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34094

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 28, 2023

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. 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. This variant has not been reported in the literature in individuals affected with IDS-related conditions. This variant is present in population databases (rs145056272, gnomAD 0.001%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 541 of the IDS protein (p.Gly541Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.32	N;.
REVEL	Uncertain	0.36
Sift	Benign	0.18	T;.
Sift4G	Benign	0.17	T;T
Polyphen		0.98	D;.
Vest4		0.29
MVP		0.76
MPC		0.50
ClinPred		0.51	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs145056272; hg19: chrX-148564309;