X-149482521-T-TA

Variant names:

• chrX-149482521-T-TA
• rs71753099
• NM_000202.8:c.*224dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000202.8(IDS):​c.*224dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., 160 hem., cov: 7)
  • Exomes 𝑓: 0.0085 (1 hom. 22 hem.)
• Consequence: IDS NM_000202.8 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.135
• Publications: 0 publications found

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

ENSG00000241489 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant X-149482521-T-TA is Benign according to our data. Variant chrX-149482521-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 1198719.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00585 (629/107570) while in subpopulation AFR AF = 0.0197 (583/29579). AF 95% confidence interval is 0.0184. There are 7 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 7. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.*224dupT		3_prime_UTR_variant	Exon 9 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.*224dupT		3_prime_UTR_variant	Exon 9 of 9		NP_001160022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.*224dupT		3_prime_UTR_variant	Exon 9 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.*224dupT		3_prime_UTR_variant	Exon 14 of 14			ENSP00000498395.1
ENSG00000241489	ENST00000422081.6	c.*224dupT		downstream_gene_variant		2		ENSP00000477056.1

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 621 AN: 107536 Hom.: 7 Cov.: 7

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00219

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00444

Gnomad NFE AF: 0.000386

Gnomad OTH AF: 0.000694

GnomAD4 exome AF: 0.00854 AC: 2477 AN: 290133 Hom.: 1 Cov.: 0 AF XY: 0.000276 AC XY: 22 AN XY: 79779

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0275 AC: 233 AN: 8488

American (AMR) AF: 0.0144 AC: 147 AN: 10235

Ashkenazi Jewish (ASJ) AF: 0.00977 AC: 78 AN: 7983

East Asian (EAS) AF: 0.0162 AC: 281 AN: 17376

South Asian (SAS) AF: 0.00595 AC: 121 AN: 20341

European-Finnish (FIN) AF: 0.00608 AC: 106 AN: 17422

Middle Eastern (MID) AF: 0.00789 AC: 9 AN: 1141

European-Non Finnish (NFE) AF: 0.00697 AC: 1325 AN: 190231

Other (OTH) AF: 0.0105 AC: 177 AN: 16916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00585 AC: 629 AN: 107570 Hom.: 7 Cov.: 7 AF XY: 0.00523 AC XY: 160 AN XY: 30584

African (AFR) AF: 0.0197 AC: 583 AN: 29579

American (AMR) AF: 0.00218 AC: 22 AN: 10070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2563

East Asian (EAS) AF: 0.000582 AC: 2 AN: 3439

South Asian (SAS) AF: 0.00 AC: 0 AN: 2554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5226

Middle Eastern (MID) AF: 0.00495 AC: 1 AN: 202

European-Non Finnish (NFE) AF: 0.000386 AC: 20 AN: 51816

Other (OTH) AF: 0.000685 AC: 1 AN: 1459

Alfa AF: 0.00 Hom.: 672

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 13, 2019

GeneDx

Significance: Likely benign

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
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs71753099; hg19: chrX-148564052;