dbSNP rs104894860: ENSG00000241489:c.-120C>T (chrX-149498301-G-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The ENST00000651111.1(ENSG00000241489):c.-120C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000914 in 1,093,788 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 (★★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

ENSG00000241489
ENST00000651111.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 4.80

Variant links:

Genes affected

ENSG00000241489 (HGNC:):

ENSG00000241489 links:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

BayesDel_addAF computational evidence supports a deleterious effect, 0.743

PP5

Variant X-149498301-G-A is Pathogenic according to our data. Variant chrX-149498301-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149498301-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8 link	c.514C>T	p.Arg172*	stop_gained	Exon 5 of 9	ENST00000340855.11	NP_000193.1	P22304-1
IDS	NM_001166550.4 link	c.244C>T	p.Arg82*	stop_gained	Exon 5 of 9		NP_001160022.1	P22304B4DGD7
IDS	NM_006123.5 link	c.514C>T	p.Arg172*	stop_gained	Exon 5 of 8		NP_006114.1	P22304-2
IDS	NR_104128.2 link	n.683C>T		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENSG00000241489	ENST00000651111.1 link	c.-120C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 10 of 14			ENSP00000498395.1	B3KWA1
IDS	ENST00000340855.11 link	c.514C>T	p.Arg172*	stop_gained	Exon 5 of 9	1	NM_000202.8	ENSP00000339801.6	P22304-1
ENSG00000241489	ENST00000651111.1 link	c.-120C>T		5_prime_UTR_variant	Exon 10 of 14			ENSP00000498395.1	B3KWA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.14e-7

AC:

AN:

1093788

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359236

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-II

Pathogenic:8Other:1

Apr 04, 2014

Division of Medical Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: research

The change c.514C>T (p.R172*) was found to be a nonsense variant, where the basic polar amino acid Arginine at 172 position was substituted by stop codon leading to early truncation of the peptide. It was found in the hemizygous condition in two non-familial patients with sever MPS-II phenotype. The patients hails from the Delhi and Bihar, India. -

Jun 07, 2024

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Null variant (PVS1_VeryStrong), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Strong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate) -

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg172*) in the IDS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDS are known to be pathogenic (PMID: 8940265, 9875019). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type II (PMID: 1639384, 7887413, 21829674, 24780617). ClinVar contains an entry for this variant (Variation ID: 10490). For these reasons, this variant has been classified as Pathogenic. -

Jan 02, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000010490 /PMID: 1639384). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 13, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderate, PM2 moderate -

Jul 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2023

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Hemizygous missense variation in exon 5 of the IDS gene that results in the termination of amino acid chain at codon 172 was detected. The observed variant c.514C>T (p.Arg172Ter) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by CADD and MutationTaster2. In summary, the variant meets our criteria to be classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jul 18, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R172* pathogenic mutation (also known as c.514C>T and 638C>T), located in coding exon 5 of the IDS gene, results from a C to T substitution at nucleotide position 514. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation was originally reported in a patient with a clinical diagnosis Hunter syndrome (Flomen RH et al. Genomics. 1992;13(3):543-550). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

not provided

Pathogenic:1

Jan 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35144014, 25525159, 33676511, 21829674, 7887413, 9875019, 1639384, 30639582, 28077157) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.89

Vest4

0.93

GERP RS

3.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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