Genetic Variant IDS:p.Phe545Tyr (chrX-149482765-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_000202.8(IDS):c.1634T>A(p.Phe545Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,199 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F545S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.473

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a chain Iduronate 2-sulfatase 14 kDa chain (size 94) in uniprot entity IDS_HUMAN there are 50 pathogenic changes around while only 5 benign (91%) in NM_000202.8

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051867187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8 link	c.1634T>A	p.Phe545Tyr	missense_variant	Exon 9 of 9	ENST00000340855.11	NP_000193.1	P22304-1
IDS	NM_001166550.4 link	c.1364T>A	p.Phe455Tyr	missense_variant	Exon 9 of 9		NP_001160022.1	P22304B4DGD7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IDS	ENST00000340855.11 link	c.1634T>A	p.Phe545Tyr	missense_variant	Exon 9 of 9	1	NM_000202.8	ENSP00000339801.6	P22304-1
ENSG00000241489	ENST00000651111.1 link	c.1001T>A	p.Phe334Tyr	missense_variant	Exon 14 of 14			ENSP00000498395.1	B3KWA1
ENSG00000241489	ENST00000422081.6 link	c.1001T>A	p.Phe334Tyr	missense_variant	Exon 9 of 9	2		ENSP00000477056.1	B3KWA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098199

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363559

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842119

Other (OTH)

AF:

0.00

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.24

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.28

T;.

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.30

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.052

T;T

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

-0.34

N;.

PhyloP100

-0.47

PrimateAI

Benign

0.33

PROVEAN

Benign

0.040

N;.

REVEL

Benign

0.22

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.12

MutPred

0.36

Gain of loop (P = 0.0097);.;

MVP

0.33

MPC

0.23

ClinPred

0.020

GERP RS

-2.7

Varity_R

0.21

gMVP

0.46

Mutation Taster

=95/5

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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X-149482765-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over