Genetic Variant NM_000202.8:c.191T>C (chrX-149504206-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000202.8(IDS):c.191T>C(p.Ile64Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.34

Variant links:

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 links:

ENSG00000241489 (HGNC:):

ENSG00000241489 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8 link	c.191T>C	p.Ile64Thr	missense_variant	Exon 2 of 9	ENST00000340855.11	NP_000193.1	P22304-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11 link	c.191T>C	p.Ile64Thr	missense_variant	Exon 2 of 9	1	NM_000202.8	ENSP00000339801.6		P22304-1
ENSG00000241489	ENST00000651111.1 link	c.-215-3169T>C		intron_variant	Intron 8 of 13			ENSP00000498395.1		B3KWA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000561

AC:

AN:

178358

Hom.:

AF XY:

0.0000158

AC XY:

AN XY:

63110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000552

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.13e-7

AC:

AN:

1095416

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360912

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191T>C (p.I64T) alteration is located in exon 2 (coding exon 2) of the IDS gene. This alteration results from a T to C substitution at nucleotide position 191, causing the isoleucine (I) at amino acid position 64 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.78

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;.;D;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

D;T;D;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;H;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;T;.

Polyphen

0.99

D;D;D;.

Vest4

0.82

MutPred

0.82

Loss of stability (P = 6e-04);Loss of stability (P = 6e-04);Loss of stability (P = 6e-04);Loss of stability (P = 6e-04);

MVP

1.0

MPC

2.1

ClinPred

0.99

GERP RS

4.9

Varity_R

0.95

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over