X-149482996-C-T

Variant names:

• chrX-149482996-C-T
• rs113993946
• NM_000202.8:c.1403G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000202.8(IDS):​c.1403G>A​(p.Arg468Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000896 in 111,552 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R468P) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 6.90
• Publications: 46 publications found

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]

IDS Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Myriad Women’s Health
• mucopolysaccharidosis type 2, attenuated form

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• mucopolysaccharidosis type 2, severe form

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000241489 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000202.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-149482996-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 92615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant X-149482996-C-T is Pathogenic according to our data. Variant chrX-149482996-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000202.8. 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
	IDS	NM_000202.8	MANE Select	c.1403G>A	p.Arg468Gln	missense	Exon 9 of 9	NP_000193.1	P22304-1
	IDS	NM_001166550.4		c.1133G>A	p.Arg378Gln	missense	Exon 9 of 9	NP_001160022.1	B4DGD7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	ENST00000340855.11	TSL:1 MANE Select	c.1403G>A	p.Arg468Gln	missense	Exon 9 of 9	ENSP00000339801.6	P22304-1
	ENSG00000241489	ENST00000651111.1		c.770G>A	p.Arg257Gln	missense	Exon 14 of 14	ENSP00000498395.1	B3KWA1
	IDS	ENST00000875674.1		c.1484G>A	p.Arg495Gln	missense	Exon 10 of 10	ENSP00000545733.1

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111552 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111552 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33760

African (AFR) AF: 0.0000326 AC: 1 AN: 30632

American (AMR) AF: 0.00 AC: 0 AN: 10521

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2669

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5987

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53104

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Mucopolysaccharidosis, MPS-II (9)
2	-	-	not provided (2)
1	-	-	Mucopolysaccharidosis type 2, severe form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.79
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		6.9
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.81		Loss of phosphorylation at S470 (P = 0.0712)
MVP		1.0
MPC		0.85
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.92
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs113993946; hg19: chrX-148564527;