rs145231211

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2

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 Conflicting classifications of pathogenicity (no stars).

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

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:5

Conservation

PhyloP100: 4.08

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 was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_000202.8

BP4

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

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 FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8 link	c.467C>A	p.Pro156Gln	missense_variant	Exon 4 of 9	ENST00000340855.11	NP_000193.1	P22304-1
IDS	NM_001166550.4 link	c.197C>A	p.Pro66Gln	missense_variant	Exon 4 of 9		NP_001160022.1	P22304B4DGD7
IDS	NM_006123.5 link	c.467C>A	p.Pro156Gln	missense_variant	Exon 4 of 8		NP_006114.1	P22304-2
IDS	NR_104128.2 link	n.636C>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.467C>A	p.Pro156Gln	missense_variant	Exon 4 of 9	1	NM_000202.8	ENSP00000339801.6		P22304-1
ENSG00000241489	ENST00000651111.1 link	c.-167C>A		5_prime_UTR_variant	Exon 9 of 14			ENSP00000498395.1		B3KWA1

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

Gnomad4 AFR exome

AF:

0.0240

AC:

616

AN:

25681

Gnomad4 AMR exome

AF:

0.00114

AC:

AN:

35185

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19212

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

30142

Gnomad4 SAS exome

AF:

0.0000186

AC:

AN:

53728

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40436

Gnomad4 NFE exome

AF:

0.0000270

AC:

AN:

814870

Gnomad4 Remaining exome

AF:

0.00128

AC:

AN:

45196

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Gnomad4 AFR

AF:

0.0264

AC:

0.0264307

AN:

0.0264307

Gnomad4 AMR

AF:

0.00258

AC:

0.00257634

AN:

0.00257634

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000944

AC:

0.0000943877

AN:

0.0000943877

Gnomad4 OTH

AF:

0.00724

AC:

0.00723684

AN:

0.00723684

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, conflicting classifications

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:criteria provided, single submitter

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

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

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

D;.

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.012

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.49

P;P

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)

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

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