Genetic Variant IDS:p.Pro550Arg (chrX-149482750-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000202.8(IDS):c.1649C>G(p.Pro550Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P550H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.15

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a chain Iduronate 2-sulfatase 14 kDa chain (size 94) in uniprot entity IDS_HUMAN there are 66 pathogenic changes around while only 5 benign (93%) in NM_000202.8

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34044886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8 link	c.1649C>G	p.Pro550Arg	missense_variant	Exon 9 of 9	ENST00000340855.11	NP_000193.1	P22304-1
IDS	NM_001166550.4 link	c.1379C>G	p.Pro460Arg	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.1649C>G	p.Pro550Arg	missense_variant	Exon 9 of 9	1	NM_000202.8	ENSP00000339801.6	P22304-1
ENSG00000241489	ENST00000651111.1 link	c.1016C>G	p.Pro339Arg	missense_variant	Exon 14 of 14			ENSP00000498395.1	B3KWA1
ENSG00000241489	ENST00000422081.6 link	c.1016C>G	p.Pro339Arg	missense_variant	Exon 9 of 9	2		ENSP00000477056.1	B3KWA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-II

Uncertain:1

Jul 02, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.47

T;T

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.34

T;T

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.50

N;.

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.14

B;.

Vest4

0.27

MutPred

0.40

Gain of solvent accessibility (P = 0.0216);.;

MVP

0.81

MPC

0.78

ClinPred

0.95

GERP RS

5.5

Varity_R

0.40

gMVP

0.71

Mutation Taster

=77/23

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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over