chrX-149482935-C-T

Variant names:

• chrX-149482935-C-T
• rs104894862
• NM_000202.8:c.1464G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PM5 PP3_Strong

The NM_000202.8(IDS):​c.1464G>A​(p.Met488Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,062 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M488V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.90
• Publications: 0 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, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia, 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 14 ACMG points.

• PS1: Transcript NM_000202.8 (IDS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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-149482936-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3256068.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	NM_000202.8	MANE Select	c.1464G>A	p.Met488Ile	missense	Exon 9 of 9	NP_000193.1
	IDS	NM_001166550.4		c.1194G>A	p.Met398Ile	missense	Exon 9 of 9	NP_001160022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	ENST00000340855.11	TSL:1 MANE Select	c.1464G>A	p.Met488Ile	missense	Exon 9 of 9	ENSP00000339801.6
	ENSG00000241489	ENST00000651111.1		c.831G>A	p.Met277Ile	missense	Exon 14 of 14	ENSP00000498395.1
	ENSG00000241489	ENST00000422081.6	TSL:2	c.831G>A	p.Met277Ile	missense	Exon 9 of 9	ENSP00000477056.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098062 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363418

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841965

Other (OTH) AF: 0.00 AC: 0 AN: 46092

GnomAD4 genome Cov.: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.84		Gain of sheet (P = 0.039)
MVP		0.96
MPC		0.83
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.89
Mutation Taster		=13/87	disease causing

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

Other links and lift over

dbSNP: rs104894862; hg19: chrX-148564466;