Genetic Variant IDS:p.Lys295Arg (chrX-149490436-T-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_000202.8(IDS):c.884A>G(p.Lys295Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,209,378 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 49 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. K295I) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., 25 hem., cov: 23)

Exomes 𝑓: 0.000078 ( 0 hom. 24 hem. )

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.882

Publications

5 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 Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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 -16 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000202.8

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-149490436-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 221212.

BP4

Computational evidence support a benign effect (MetaRNN=0.03931564).

BP6

Variant X-149490436-T-C is Benign according to our data. Variant chrX-149490436-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 791679.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 = 0.000663 (74/111626) while in subpopulation AFR AF = 0.00225 (69/30611). AF 95% confidence interval is 0.00183. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 25 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	UniProt
IDS	NM_000202.8	MANE Select	c.884A>G	p.Lys295Arg	missense	Exon 7 of 9	NP_000193.1	P22304-1
IDS	NM_001166550.4		c.614A>G	p.Lys205Arg	missense	Exon 7 of 9	NP_001160022.1	B4DGD7
IDS	NM_006123.5		c.884A>G	p.Lys295Arg	missense	Exon 7 of 8	NP_006114.1	P22304-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDS	ENST00000340855.11	TSL:1 MANE Select	c.884A>G	p.Lys295Arg	missense	Exon 7 of 9	ENSP00000339801.6	P22304-1
IDS	ENST00000370441.8	TSL:1	c.884A>G	p.Lys295Arg	missense	Exon 7 of 8	ENSP00000359470.4	P22304-2
ENSG00000241489	ENST00000651111.1		c.251A>G	p.Lys84Arg	missense	Exon 12 of 14	ENSP00000498395.1	B3KWA1

Frequencies

GnomAD3 genomes

AF:

0.000663

AC:

AN:

111626

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00225

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000475

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000164

AC:

AN:

183172

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00198

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000783

AC:

AN:

1097752

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

363118

show subpopulations

African (AFR)

AF:

0.00265

AC:

AN:

26397

American (AMR)

AF:

0.000114

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40473

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841754

Other (OTH)

AF:

0.000174

AC:

AN:

46078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.000663

AC:

AN:

111626

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

33816

show subpopulations

African (AFR)

AF:

0.00225

AC:

AN:

30611

American (AMR)

AF:

0.000475

AC:

AN:

10534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53125

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

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:

0.000285

Hom.:

Bravo

AF:

0.000869

ESP6500AA

AF:

0.00287

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Mucopolysaccharidosis, MPS-II (1)

Mucopolysaccharidosis, MPS-III-A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.039

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

0.66

PhyloP100

0.88

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.83

REVEL

Uncertain

0.36

Sift

Benign

0.44

Sift4G

Benign

0.69

Polyphen

0.025

Vest4

0.20

MVP

0.82

MPC

0.17

ClinPred

0.0097

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.61

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over