rs370125505

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_000202.8(IDS):c.1144G>C(p.Asp382His) variant causes a missense change. The variant allele was found at a frequency of 0.000014 in 1,210,162 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000073 ( 0 hom. 1 hem. )

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.90

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 Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.89

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDS	NM_000202.8 linkuse as main transcript	c.1144G>C	p.Asp382His	missense_variant	8/9	ENST00000340855.11	NP_000193.1	P22304-1
IDS	NM_001166550.4 linkuse as main transcript	c.874G>C	p.Asp292His	missense_variant	8/9		NP_001160022.1	P22304B4DGD7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IDS	ENST00000340855.11 linkuse as main transcript	c.1144G>C	p.Asp382His	missense_variant	8/9	1	NM_000202.8	ENSP00000339801.6	P22304-1
ENSG00000241489	ENST00000651111.1 linkuse as main transcript	c.511G>C	p.Asp171His	missense_variant	13/14			ENSP00000498395.1	B3KWA1
ENSG00000241489	ENST00000422081.6 linkuse as main transcript	c.511G>C	p.Asp171His	missense_variant	8/9	2		ENSP00000477056.1	B3KWA1
ENSG00000241489	ENST00000441880.1 linkuse as main transcript	n.251G>C		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000803

AC:

AN:

112066

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

34262

show subpopulations

Gnomad AFR

AF:

0.0000975

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000282

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183485

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67913

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.0000365

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:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.00000729

AC:

AN:

1098096

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363450

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000803

AC:

AN:

112066

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

34262

show subpopulations

Gnomad4 AFR

AF:

0.0000975

Gnomad4 AMR

AF:

0.000282

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000564

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-II

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 22, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 382 of the IDS protein (p.Asp382His). This variant is present in population databases (rs370125505, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with IDS-related conditions. ClinVar contains an entry for this variant (Variation ID: 568588). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 11, 2020	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2015

The p.D382H variant (also known as c.1144G>C), located in coding exon 8 of the IDS gene, results from a G to C substitution at nucleotide position 1144. The aspartic acid at codon 382 is replaced by histidine, an amino acid with similar properties. This variant has been detected in conjunction with a pathogenic mutation in GRIA3 gene by our laboratory. This variant was previously reported in the SNPDatabase as rs370125505. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele was absent out of 2443 total male alleles studied. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Mucopolysaccharidosis, MPS-III-A

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

D;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.8

D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0060

D;.

Sift4G

Uncertain

0.023

D;D

Polyphen

1.0

D;.

Vest4

0.55

MVP

1.0

MPC

0.85

ClinPred

0.64

GERP RS

4.4

Varity_R

0.43

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.25

Position offset: -36

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