rs61736892

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PM1PM5BP4_StrongBS1_SupportingBS2

The NM_000202.8(IDS):c.641C>T(p.Thr214Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,210,141 control chromosomes in the GnomAD database, including 50 homozygotes. There are 819 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T214R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.014 ( 28 hom., 432 hem., cov: 24)

Exomes 𝑓: 0.0015 ( 22 hom. 387 hem. )

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2B:12

Conservation

PhyloP100: 0.409

Publications

9 publications found

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 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

IDS links:

ENSG00000241489 (HGNC:):

ENSG00000241489 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000202.8

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-149498174-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3255786.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036536455).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (1555/112243) while in subpopulation AFR AF = 0.0468 (1443/30831). AF 95% confidence interval is 0.0448. There are 28 homozygotes in GnomAd4. There are 432 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 28 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8 link	c.641C>T	p.Thr214Met	missense_variant	Exon 5 of 9	ENST00000340855.11	NP_000193.1	P22304-1
IDS	NM_001166550.4 link	c.371C>T	p.Thr124Met	missense_variant	Exon 5 of 9		NP_001160022.1	P22304B4DGD7
IDS	NM_006123.5 link	c.641C>T	p.Thr214Met	missense_variant	Exon 5 of 8		NP_006114.1	P22304-2
IDS	NR_104128.2 link	n.810C>T		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11 link	c.641C>T	p.Thr214Met	missense_variant	Exon 5 of 9	1	NM_000202.8	ENSP00000339801.6		P22304-1
ENSG00000241489	ENST00000651111.1 link	c.8C>T	p.Thr3Met	missense_variant	Exon 10 of 14			ENSP00000498395.1		B3KWA1

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

1551

AN:

112191

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0468

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00891

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00796

GnomAD2 exomes

AF:

0.00398

AC:

730

AN:

183456

AF XY:

0.00256

show subpopulations

Gnomad AFR exome

AF:

0.0499

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000610

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00145

AC:

1596

AN:

1097898

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

387

AN XY:

363260

show subpopulations

African (AFR)

AF:

0.0500

AC:

1321

AN:

26394

American (AMR)

AF:

0.00287

AC:

101

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.000240

AC:

AN:

54142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0000368

AC:

AN:

841821

Other (OTH)

AF:

0.00269

AC:

124

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

135

203

270

338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0139

AC:

1555

AN:

112243

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

432

AN XY:

34439

show subpopulations

African (AFR)

AF:

0.0468

AC:

1443

AN:

30831

American (AMR)

AF:

0.00890

AC:

AN:

10674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2701

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6144

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

53249

Other (OTH)

AF:

0.00786

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0173

Hom.:

295

Bravo

AF:

0.0157

ESP6500AA

AF:

0.0480

AC:

184

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00451

AC:

547

EpiCase

AF:

0.000382

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-II

Pathogenic:2Benign:5

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 02, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2024

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense change at the same amino acid residue as a pathogenic variant (PM5_Supporting), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate), Multiple lines of computational evidence suggest no impact on gene or gene product (BP4_Supporting) -

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 07, 2010

IIFP, CONICET-UNLP

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The patient with this genetic variant is hemizygous for the variant in IDS gene: c.641C>T It is an X-linked disorder The disorder is Hunter disease or mucopolysaccharidosis type II The patient has a deficient activity of Iduronate 2 sulfatase in dried blood filter paper test. And normal activity of another sulfatase ruling out multiple sulfatase deficiency. He had two other family members affected from the same disorder, from the maternal side: a maternal uncle and maternal grand uncle. Both have died because of Hunter disease. Clinical manifestations are: Cifosis, short neck, disostosis multiplex, coarse face, hernia, macroglosia, claw hand, hepatosplenomegaly -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 08, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21605424, 27884173, 27695081, 27896113, 31019283, 32448126) -

Jun 26, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The IDS c.641C>T (p.Thr214Met) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 444/87744 control chromosomes (12 homozygotes, 100 hemizygotes) at a frequency of 0.0050602, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic IDS variant (0.0028868), suggesting this variant is likely a benign polymorphism. A publication, Chkioua_2011, cites the variant in an affected individual, who was homozygous for the pathogenic R88P variant. This variant also co-occurred with a pathogenic variant, c.1402C>T (p.R468W) in a sample tested at our laboratory. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 27, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;.

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.69

T;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

0.79

N;N;.

PhyloP100

0.41

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.7

N;N;.

REVEL

Uncertain

0.32

Sift

Benign

0.11

T;T;.

Sift4G

Benign

0.11

T;T;T

Polyphen

0.99

D;D;.

Vest4

0.10

MVP

0.77

MPC

0.23

ClinPred

0.015

GERP RS

1.7

Varity_R

0.030

gMVP

0.65

Mutation Taster

=66/34

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over