rs61736892

Positions:

• chrX-149498174-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM5 BP4_Strong BS1_Supporting BS2

The NM_000202.8(IDS):​c.641C>T​(p.Thr214Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,210,141 control chromosomes in the GnomAD database, including 50 homozygotes. There are 819 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T214R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.014 (28 hom., 432 hem., cov: 24)
  • Exomes 𝑓: 0.0015 (22 hom. 387 hem.)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:12
• Conservation: PhyloP100: 0.409

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000202.8
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-149498174-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3255786.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036536455).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0139 (1555/112243) while in subpopulation AFR AF= 0.0468 (1443/30831). AF 95% confidence interval is 0.0448. There are 28 homozygotes in gnomad4. There are 432 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDS	NM_000202.8	c.641C>T	p.Thr214Met	missense_variant	5/9	ENST00000340855.11
IDS	NM_001166550.4	c.371C>T	p.Thr124Met	missense_variant	5/9
IDS	NM_006123.5	c.641C>T	p.Thr214Met	missense_variant	5/8
IDS	NR_104128.2	n.810C>T		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.641C>T	p.Thr214Met	missense_variant	5/9	1	NM_000202.8	P1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 1551 AN: 112191 Hom.: 28 Cov.: 24 AF XY: 0.0124 AC XY: 427 AN XY: 34377

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00891

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00796

GnomAD3 exomes AF: 0.00398 AC: 730 AN: 183456 Hom.: 17 AF XY: 0.00256 AC XY: 174 AN XY: 67888

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000610

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00145 AC: 1596 AN: 1097898 Hom.: 22 Cov.: 30 AF XY: 0.00107 AC XY: 387 AN XY: 363260

Gnomad4 AFR exome AF: 0.0500

Gnomad4 AMR exome AF: 0.00287

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000368

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.0139 AC: 1555 AN: 112243 Hom.: 28 Cov.: 24 AF XY: 0.0125 AC XY: 432 AN XY: 34439

Gnomad4 AFR AF: 0.0468

Gnomad4 AMR AF: 0.00890

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000751

Gnomad4 OTH AF: 0.00786

Alfa AF: 0.00629 Hom.: 43

Bravo AF: 0.0157

ESP6500AA AF: 0.0480 AC: 184

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00451 AC: 547

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:2 Benign:5

Likely pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jun 07, 2024	Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense change at the same amino acid residue as a pathogenic variant (PM5_Supporting), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate), Multiple lines of computational evidence suggest no impact on gene or gene product (BP4_Supporting) -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Pathogenic, criteria provided, single submitter	research	IIFP, CONICET-UNLP	Dec 07, 2010	The patient with this genetic variant is hemizygous for the variant in IDS gene: c.641C>T It is an X-linked disorder The disorder is Hunter disease or mucopolysaccharidosis type II The patient has a deficient activity of Iduronate 2 sulfatase in dried blood filter paper test. And normal activity of another sulfatase ruling out multiple sulfatase deficiency. He had two other family members affected from the same disorder, from the maternal side: a maternal uncle and maternal grand uncle. Both have died because of Hunter disease. Clinical manifestations are: Cifosis, short neck, disostosis multiplex, coarse face, hernia, macroglosia, claw hand, hepatosplenomegaly -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2017	Variant summary: The IDS c.641C>T (p.Thr214Met) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 444/87744 control chromosomes (12 homozygotes, 100 hemizygotes) at a frequency of 0.0050602, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic IDS variant (0.0028868), suggesting this variant is likely a benign polymorphism. A publication, Chkioua_2011, cites the variant in an affected individual, who was homozygous for the pathogenic R88P variant. This variant also co-occurred with a pathogenic variant, c.1402C>T (p.R468W) in a sample tested at our laboratory. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 21605424, 27884173, 27695081, 27896113, 31019283, 32448126) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2014

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.79	N;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.11	T;T;.
Sift4G	Benign	0.11	T;T;T
Polyphen		0.99	D;D;.
Vest4		0.10
MVP		0.77
MPC		0.23
ClinPred		0.015	T
GERP RS		1.7
Varity_R		0.030
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61736892; hg19: chrX-148579705;