Variant rs199422227 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000202.8(IDS):c.1327C>T(p.Arg443Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 111,520 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: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Consequence

IDS
NM_000202.8 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.555

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-149483072-G-A is Pathogenic according to our data. Variant chrX-149483072-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149483072-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDS	NM_000202.8 linkuse as main transcript	c.1327C>T	p.Arg443Ter	stop_gained	9/9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4 linkuse as main transcript	c.1057C>T	p.Arg353Ter	stop_gained	9/9		NP_001160022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11 linkuse as main transcript	c.1327C>T	p.Arg443Ter	stop_gained	9/9	1	NM_000202.8	ENSP00000339801	P1	P22304-1

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111468

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33662

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111520

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33724

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000105

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-II

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -
Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Pathogenic, criteria provided, single submitter	research	IIFP, CONICET-UNLP	Dec 13, 2012	- -
Pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jun 07, 2024	Null variant (PVS1_Strong), In vitro or in vivo functional studies supportive of a damaging effect (PS3_Moderate), 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), Cosegregation with disease in multiple affected family members (PP1_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 29, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 10486). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis II (PMID: 1303211, 18500569, 21291454, 21829674, 27146977). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg443*) in the IDS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 108 amino acid(s) of the IDS protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	- -

Mucopolysaccharidosis, MPS-III-A

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 08, 2020

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 20, 2021

ACMG categories: PVS1,PM2,PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

FATHMM_MKL

Benign

0.17

MutationTaster

Benign

1.0

A;A;A

Vest4

0.57

GERP RS

0.79

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