rs141720810

chrX-149496444-G-AchrX-149496444-G-CchrX-149496444-G-T

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.781C>T(p.Pro261Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 112,131 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P261A) has been classified as Likely benign.

• 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: -0.0170

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000202.8
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24034512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDS	NM_000202.8	c.781C>T	p.Pro261Ser	missense_variant	6/9	ENST00000340855.11
IDS	NM_001166550.4	c.511C>T	p.Pro171Ser	missense_variant	6/9
IDS	NM_006123.5	c.781C>T	p.Pro261Ser	missense_variant	6/8
IDS	NR_104128.2	n.950C>T		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.781C>T	p.Pro261Ser	missense_variant	6/9	1	NM_000202.8	P1

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112131 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34283

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.: 30

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112131 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34283

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: 0.00000756

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

Invitae

Jul 16, 2020

This sequence change replaces proline with serine at codon 261 of the IDS protein (p.Pro261Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IDS-related conditions. 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) performed at Invitae indicates that this missense variant is expected to disrupt 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	0.070
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	7.3
Dann	Benign	0.92
DEOGEN2	Uncertain	0.74	D;.;.
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.40	N;N;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.89	N;N;.
REVEL	Uncertain	0.36
Sift	Benign	1.0	T;T;.
Sift4G	Benign	0.88	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.21
MutPred		0.43		Loss of catalytic residue at P260 (P = 0.0121);Loss of catalytic residue at P260 (P = 0.0121);.;
MVP		0.71
MPC		0.21
ClinPred		0.079	T
GERP RS		2.8
Varity_R		0.14
gMVP		0.65

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: rs141720810; hg19: chrX-148577975;