Genetic Variant IDS:p.Pro156Gln (chrX-149500989-G-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000202.8(IDS):c.467C>A(p.Pro156Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,179,632 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. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 8 hom., 231 hem., cov: 23)

Exomes 𝑓: 0.00069 ( 2 hom. 198 hem. )

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:5

Conservation

PhyloP100: 4.08

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 -18 ACMG points.

PM1

In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_000202.8

BP4

Computational evidence support a benign effect (MetaRNN=0.016393512).

BP6

Variant X-149500989-G-T is Benign according to our data. Variant chrX-149500989-G-T is described in ClinVar as Benign. ClinVar VariationId is 457346.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 = 0.00763 (848/111115) while in subpopulation AFR AF = 0.0264 (805/30457). AF 95% confidence interval is 0.0249. There are 8 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000202.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IDS	NM_000202.8	MANE Select	c.467C>A	p.Pro156Gln	missense	Exon 4 of 9	NP_000193.1
IDS	NM_001166550.4		c.197C>A	p.Pro66Gln	missense	Exon 4 of 9	NP_001160022.1
IDS	NM_006123.5		c.467C>A	p.Pro156Gln	missense	Exon 4 of 8	NP_006114.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IDS	ENST00000340855.11	TSL:1 MANE Select	c.467C>A	p.Pro156Gln	missense	Exon 4 of 9	ENSP00000339801.6
IDS	ENST00000370441.8	TSL:1	c.467C>A	p.Pro156Gln	missense	Exon 4 of 8	ENSP00000359470.4
IDS	ENST00000466323.5	TSL:1	n.467C>A		non_coding_transcript_exon	Exon 4 of 9	ENSP00000418264.1

Frequencies

GnomAD3 genomes

AF:

0.00761

AC:

845

AN:

111065

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0264

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00258

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:

0.0000944

Gnomad OTH

AF:

0.00733

GnomAD2 exomes

AF:

0.00225

AC:

413

AN:

183371

AF XY:

0.00145

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:

0.000694

AC:

742

AN:

1068517

Hom.:

Cov.:

AF XY:

0.000585

AC XY:

198

AN XY:

338725

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:

616

AN:

25681

American (AMR)

AF:

0.00114

AC:

AN:

35185

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19212

East Asian (EAS)

AF:

0.00

AC:

AN:

30142

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40436

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

4067

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

814870

Other (OTH)

AF:

0.00128

AC:

AN:

45196

⚠️ 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: 0.398

Heterozygous variant carriers

118

147

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:

0.00763

AC:

848

AN:

111115

Hom.:

Cov.:

AF XY:

0.00692

AC XY:

231

AN XY:

33363

show subpopulations

African (AFR)

AF:

0.0264

AC:

805

AN:

30457

American (AMR)

AF:

0.00258

AC:

AN:

10480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3567

South Asian (SAS)

AF:

0.00

AC:

AN:

2636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0000944

AC:

AN:

52973

Other (OTH)

AF:

0.00724

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

126

157

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:

0.00147

Hom.:

Bravo

AF:

0.00910

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0318

AC:

122

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00265

AC:

322

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-II

Pathogenic:1Benign:1

Jun 07, 2024

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

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:literature only

Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), 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_Strong)

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Sep 27, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.016

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.4

PhyloP100

4.1

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.71

Sift

Uncertain

0.012

Sift4G

Benign

0.12

Polyphen

0.49

Vest4

0.52

MVP

0.93

MPC

2.1

ClinPred

0.093

GERP RS

3.6

Varity_R

0.62

gMVP

0.96

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over