chrX-149500993-A-G

Variant names:

• chrX-149500993-A-G
• NM_000202.8:c.463T>C
• IDS p.Phe155Leu

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP5_Moderate BP4

The NM_000202.8(IDS):​c.463T>C​(p.Phe155Leu) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F155F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.237
• 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 Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Myriad Women's Health, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in NM_000202.8
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-149500993-A-G is Pathogenic according to our data. Variant chrX-149500993-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3255745.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.049573243). . Strength limited to SUPPORTING due to the PP5.

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.463T>C	p.Phe155Leu	missense	Exon 4 of 9	NP_000193.1	P22304-1
	IDS	NM_001166550.4		c.193T>C	p.Phe65Leu	missense	Exon 4 of 9	NP_001160022.1	B4DGD7
	IDS	NM_006123.5		c.463T>C	p.Phe155Leu	missense	Exon 4 of 8	NP_006114.1	P22304-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	ENST00000340855.11	TSL:1 MANE Select	c.463T>C	p.Phe155Leu	missense	Exon 4 of 9	ENSP00000339801.6	P22304-1
	IDS	ENST00000370441.8	TSL:1	c.463T>C	p.Phe155Leu	missense	Exon 4 of 8	ENSP00000359470.4	P22304-2
	ENSG00000241489	ENST00000651111.1		c.-171T>C		5_prime_UTR	Exon 9 of 14	ENSP00000498395.1	B3KWA1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1073110 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 342302

African (AFR) AF: 0.00 AC: 0 AN: 25939

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19239

East Asian (EAS) AF: 0.00 AC: 0 AN: 30165

South Asian (SAS) AF: 0.00 AC: 0 AN: 53805

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4080

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 818912

Other (OTH) AF: 0.00 AC: 0 AN: 45311

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mucopolysaccharidosis, MPS-II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.74
DANN	Benign	0.74
DEOGEN2	Uncertain	0.60	D
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.050	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	-0.97	N
PhyloP100		-0.24
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.27	N
REVEL	Uncertain	0.30
Sift	Benign	0.70	T
Sift4G	Benign	0.68	T
Varity_R		0.17
gMVP		0.88
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-148582524;