chrX-149501018-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000651111.1(ENSG00000241489):c.-196C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,165,083 control chromosomes in the GnomAD database, including 54,181 homozygotes. There are 119,286 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 4367 hom., 9370 hem., cov: 22)

Exomes 𝑓: 0.35 ( 49814 hom. 109916 hem. )

Consequence

ENSG00000241489
ENST00000651111.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.771

Publications

22 publications found

Variant links:

Genes affected

ENSG00000241489 (HGNC:):

ENSG00000241489 links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant X-149501018-G-A is Benign according to our data. Variant chrX-149501018-G-A is described in ClinVar as Benign. ClinVar VariationId is 92619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IDS	NM_000202.8 link	c.438C>T	p.Thr146Thr	synonymous_variant	Exon 4 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4 link	c.168C>T	p.Thr56Thr	synonymous_variant	Exon 4 of 9		NP_001160022.1
IDS	NM_006123.5 link	c.438C>T	p.Thr146Thr	synonymous_variant	Exon 4 of 8		NP_006114.1
IDS	NR_104128.2 link	n.607C>T		non_coding_transcript_exon_variant	Exon 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ENSG00000241489	ENST00000651111.1 link	c.-196C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 9 of 14			ENSP00000498395.1
IDS	ENST00000340855.11 link	c.438C>T	p.Thr146Thr	synonymous_variant	Exon 4 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1 link	c.-196C>T		5_prime_UTR_variant	Exon 9 of 14			ENSP00000498395.1

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

34181

AN:

109470

Hom.:

4371

Cov.:

show subpopulations

Gnomad AFR

AF:

0.252

Gnomad AMI

AF:

0.407

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.331

Gnomad EAS

AF:

0.00283

Gnomad SAS

AF:

0.0690

Gnomad FIN

AF:

0.299

Gnomad MID

AF:

0.433

Gnomad NFE

AF:

0.390

Gnomad OTH

AF:

0.325

GnomAD2 exomes

AF:

0.275

AC:

50217

AN:

182867

AF XY:

0.273

show subpopulations

Gnomad AFR exome

AF:

0.255

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.334

Gnomad EAS exome

AF:

0.00115

Gnomad FIN exome

AF:

0.317

Gnomad NFE exome

AF:

0.391

Gnomad OTH exome

AF:

0.307

GnomAD4 exome

AF:

0.347

AC:

366356

AN:

1055561

Hom.:

49814

Cov.:

AF XY:

0.328

AC XY:

109916

AN XY:

335471

show subpopulations

African (AFR)

AF:

0.245

AC:

6245

AN:

25485

American (AMR)

AF:

0.165

AC:

5799

AN:

35161

Ashkenazi Jewish (ASJ)

AF:

0.336

AC:

6417

AN:

19114

East Asian (EAS)

AF:

0.00110

AC:

AN:

30099

South Asian (SAS)

AF:

0.0926

AC:

4960

AN:

53538

European-Finnish (FIN)

AF:

0.318

AC:

12791

AN:

40285

Middle Eastern (MID)

AF:

0.313

AC:

1269

AN:

4051

European-Non Finnish (NFE)

AF:

0.392

AC:

314445

AN:

803062

Other (OTH)

AF:

0.322

AC:

14397

AN:

44766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

7063

14126

21188

28251

35314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9970

19940

29910

39880

49850

<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:

0.312

AC:

34176

AN:

109522

Hom.:

4367

Cov.:

AF XY:

0.294

AC XY:

9370

AN XY:

31922

show subpopulations

African (AFR)

AF:

0.252

AC:

7550

AN:

30012

American (AMR)

AF:

0.249

AC:

2576

AN:

10335

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

870

AN:

2626

East Asian (EAS)

AF:

0.00283

AC:

AN:

3528

South Asian (SAS)

AF:

0.0681

AC:

176

AN:

2585

European-Finnish (FIN)

AF:

0.299

AC:

1689

AN:

5640

Middle Eastern (MID)

AF:

0.420

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.390

AC:

20464

AN:

52414

Other (OTH)

AF:

0.319

AC:

478

AN:

1497

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

823

1645

2468

3290

4113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.339

Hom.:

10442

Bravo

AF:

0.308

EpiCase

AF:

0.397

EpiControl

AF:

0.393

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 08, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Feb 03, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 08, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The IDS c.438C>T (p.Thr146Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 24360/87524 control chromosomes (including 2605 homozygotes and 9302 hemizygotes) at a frequency of 0.2783237, which is approximately 96 times the estimated maximal expected allele frequency of a pathogenic IDS variant (0.0028868). Thus this variant is a common polymorphism found in the general population. In addition, multiple clinical diagnostic laboratories have classified this variant as benign and the variant is considered a common polymorphism in the literature. Taken together, this variant is classified as Benign. -

Jun 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mucopolysaccharidosis, MPS-II

Benign:4

May 31, 2007

IIFP, CONICET-UNLP

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 24, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.5

(source)

DANN

Benign

0.74

PhyloP100

0.77

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

0.0

SpliceAI score (max)

0.010

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