X-149504161-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 5P and 16B. PM1PM5PP3BP6_Very_StrongBS1BS2

The NM_000202.8(IDS):c.236C>G(p.Ala79Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000921 in 1,205,506 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000091 ( 0 hom. 32 hem. )

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.15

Publications

2 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 -11 ACMG points.

PM1

In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000202.8

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-149504161-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3256102.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

BP6

Variant X-149504161-G-C is Benign according to our data. Variant chrX-149504161-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1166377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000979 (11/112314) while in subpopulation NFE AF = 0.000188 (10/53224). AF 95% confidence interval is 0.000102. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IDS	NM_000202.8 link	c.236C>G	p.Ala79Gly	missense_variant	Exon 2 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4 link	c.10C>G	p.Arg4Gly	missense_variant	Exon 2 of 9		NP_001160022.1
IDS	NM_006123.5 link	c.236C>G	p.Ala79Gly	missense_variant	Exon 2 of 8		NP_006114.1
IDS	NR_104128.2 link	n.405C>G		non_coding_transcript_exon_variant	Exon 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11 link	c.236C>G	p.Ala79Gly	missense_variant	Exon 2 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1 link	c.-215-3124C>G		intron_variant	Intron 8 of 13			ENSP00000498395.1

Frequencies

GnomAD3 genomes

AF:

0.0000979

AC:

AN:

112314

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000862

AC:

AN:

173948

AF XY:

0.0000672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000130

Gnomad NFE exome

AF:

0.000170

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000915

AC:

100

AN:

1093192

Hom.:

Cov.:

AF XY:

0.0000891

AC XY:

AN XY:

358972

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26340

American (AMR)

AF:

0.0000286

AC:

AN:

34914

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19285

East Asian (EAS)

AF:

0.00

AC:

AN:

30122

South Asian (SAS)

AF:

0.00

AC:

AN:

53402

European-Finnish (FIN)

AF:

0.000198

AC:

AN:

40315

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.000106

AC:

AN:

838773

Other (OTH)

AF:

0.0000435

AC:

AN:

45925

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000979

AC:

AN:

112314

Hom.:

Cov.:

AF XY:

0.0000870

AC XY:

AN XY:

34494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30868

American (AMR)

AF:

0.00

AC:

AN:

10652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.00

AC:

AN:

2753

European-Finnish (FIN)

AF:

0.000162

AC:

AN:

6172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000188

AC:

AN:

53224

Other (OTH)

AF:

0.00

AC:

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000327

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Dec 30, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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-II

Benign:1

Nov 05, 2024

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

Uncertain

0.44

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;D;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;M;.;.

PhyloP100

7.2

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Uncertain

0.022

D;D;T;.

Vest4

0.67

ClinPred

0.55

GERP RS

4.0

Varity_R

0.92

gMVP

0.94

Mutation Taster

=74/26

polymorphism

(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