rs145231211

Variant summary

Our verdict is Benign. Variant got -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 B:4

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 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 id 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 male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IDS	NM_000202.8 linkuse as main transcript	c.467C>A	p.Pro156Gln	missense_variant	4/9	ENST00000340855.11
IDS	NM_001166550.4 linkuse as main transcript	c.197C>A	p.Pro66Gln	missense_variant	4/9
IDS	NM_006123.5 linkuse as main transcript	c.467C>A	p.Pro156Gln	missense_variant	4/8
IDS	NR_104128.2 linkuse as main transcript	n.636C>A		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11 linkuse as main transcript	c.467C>A	p.Pro156Gln	missense_variant	4/9	1	NM_000202.8	P1	P22304-1

Frequencies

GnomAD3 genomes

AF:

0.00761

AC:

845

AN:

111065

Hom.:

Cov.:

AF XY:

0.00685

AC XY:

228

AN XY:

33303

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

GnomAD3 exomes

AF:

0.00225

AC:

413

AN:

183371

Hom.:

AF XY:

0.00145

AC XY:

AN XY:

67819

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 SAS 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

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00128

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

Gnomad4 AMR

AF:

0.00258

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000944

Gnomad4 OTH

AF:

0.00724

Alfa

AF:

0.000528

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: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2016

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 21, 2020

- -

not provided

Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 27, 2017

- -

Mucopolysaccharidosis, MPS-II

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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

MutationTaster

Benign

0.000012

P;P;P;P

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

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