rs61736892

Positions:

chrX-149498174-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDS	NM_000202.8 linkuse as main transcript	c.641C>T	p.Thr214Met	missense_variant	5/9	ENST00000340855.11	NP_000193.1	P22304-1
IDS	NM_001166550.4 linkuse as main transcript	c.371C>T	p.Thr124Met	missense_variant	5/9		NP_001160022.1	P22304B4DGD7
IDS	NM_006123.5 linkuse as main transcript	c.641C>T	p.Thr214Met	missense_variant	5/8		NP_006114.1	P22304-2
IDS	NR_104128.2 linkuse as main transcript	n.810C>T		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11 linkuse as main transcript	c.641C>T	p.Thr214Met	missense_variant	5/9	1	NM_000202.8	ENSP00000339801.6		P22304-1
ENSG00000241489	ENST00000651111.1 linkuse as main transcript	c.8C>T	p.Thr3Met	missense_variant	10/14			ENSP00000498395.1		B3KWA1

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

1551

AN:

112191

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

427

AN XY:

34377

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

GnomAD3 exomes

AF:

0.00398

AC:

730

AN:

183456

Hom.:

AF XY:

0.00256

AC XY:

174

AN XY:

67888

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 SAS exome

AF:

0.0000524

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

Gnomad4 AFR exome

AF:

0.0500

Gnomad4 AMR exome

AF:

0.00287

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000240

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000368

Gnomad4 OTH exome

AF:

0.00269

GnomAD4 genome

AF:

0.0139

AC:

1555

AN:

112243

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

432

AN XY:

34439

show subpopulations

Gnomad4 AFR

AF:

0.0468

Gnomad4 AMR

AF:

0.00890

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000751

Gnomad4 OTH

AF:

0.00786

Alfa

AF:

0.00629

Hom.:

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

Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	research	IIFP, CONICET-UNLP	Dec 07, 2010	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 -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jun 07, 2024	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) -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 21605424, 27884173, 27695081, 27896113, 31019283, 32448126) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2014

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

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;.

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

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

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