chrX-149500991-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 6P and 20B. PS1PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000202.8(IDS):c.465T>A(p.Phe155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,183,684 control chromosomes in the GnomAD database, including 10 homozygotes. There are 429 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F155F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0076 ( 8 hom., 231 hem., cov: 24)

Exomes 𝑓: 0.00069 ( 2 hom. 198 hem. )

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.117

Publications

1 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: Benign. The variant received -14 ACMG points.

PS1

Transcript NM_000202.8 (IDS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in NM_000202.8

BP4

Computational evidence support a benign effect (MetaRNN=0.0029900074).

BP6

Variant X-149500991-A-T is Benign according to our data. Variant chrX-149500991-A-T is described in ClinVar as Benign. ClinVar VariationId is 457354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0076 (848/111555) while in subpopulation AFR AF = 0.0263 (805/30590). AF 95% confidence interval is 0.0248. There are 8 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IDS	NM_000202.8 link	c.465T>A	p.Phe155Leu	missense_variant	Exon 4 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4 link	c.195T>A	p.Phe65Leu	missense_variant	Exon 4 of 9		NP_001160022.1
IDS	NM_006123.5 link	c.465T>A	p.Phe155Leu	missense_variant	Exon 4 of 8		NP_006114.1
IDS	NR_104128.2 link	n.634T>A		non_coding_transcript_exon_variant	Exon 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11 link	c.465T>A	p.Phe155Leu	missense_variant	Exon 4 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1 link	c.-169T>A		5_prime_UTR_variant	Exon 9 of 14			ENSP00000498395.1

Frequencies

GnomAD3 genomes

AF:

0.00758

AC:

845

AN:

111502

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00256

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:

0.0000942

Gnomad OTH

AF:

0.00731

GnomAD2 exomes

AF:

0.00225

AC:

413

AN:

183380

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.0287

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000732

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000693

AC:

743

AN:

1072129

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

198

AN XY:

341811

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0240

AC:

618

AN:

25752

American (AMR)

AF:

0.00111

AC:

AN:

35191

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19241

East Asian (EAS)

AF:

0.00

AC:

AN:

30157

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40462

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

0.0000269

AC:

AN:

818165

Other (OTH)

AF:

0.00128

AC:

AN:

45285

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.396

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00760

AC:

848

AN:

111555

Hom.:

Cov.:

AF XY:

0.00684

AC XY:

231

AN XY:

33753

show subpopulations

African (AFR)

AF:

0.0263

AC:

805

AN:

30590

American (AMR)

AF:

0.00256

AC:

AN:

10544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.00

AC:

AN:

2642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000942

AC:

AN:

53055

Other (OTH)

AF:

0.00722

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

114

143

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:

0.000599

Hom.:

Bravo

AF:

0.00910

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0310

AC:

119

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00265

AC:

322

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 27, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 20, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 15, 2016

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. -

Mucopolysaccharidosis, MPS-III-A

Benign:1

Jul 21, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

IDS-related disorder

Benign:1

Jan 21, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Mucopolysaccharidosis, MPS-II

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.24

CADD

Benign

5.8

(source)

DANN

Benign

0.80

DEOGEN2

Uncertain

0.60

D;.

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

-0.97

N;N

PhyloP100

0.12

PrimateAI

Benign

0.32

PROVEAN

Benign

0.27

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.70

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.0

B;B

Vest4

0.13

MutPred

0.45

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);

MVP

0.49

MPC

1.2

ClinPred

0.0036

GERP RS

-3.9

Varity_R

0.18

gMVP

0.88

Mutation Taster

=297/3

polymorphism (auto)

(source)

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

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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