X-149483072-G-T

Variant names:

• chrX-149483072-G-T
• rs199422227
• NM_000202.8:c.1327C>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000202.8(IDS):​c.1327C>A​(p.Arg443Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000083 in 1,205,102 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: IDS NM_000202.8 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.555
• Publications: 23 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-149483072-G-T is Benign according to our data. Variant chrX-149483072-G-T is described in ClinVar as Benign. ClinVar VariationId is 2140184.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.555 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.1327C>A	p.Arg443Arg	synonymous_variant	Exon 9 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.1057C>A	p.Arg353Arg	synonymous_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.1327C>A	p.Arg443Arg	synonymous_variant	Exon 9 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.694C>A	p.Arg232Arg	synonymous_variant	Exon 14 of 14			ENSP00000498395.1
ENSG00000241489	ENST00000422081.6	c.694C>A	p.Arg232Arg	synonymous_variant	Exon 9 of 9	2		ENSP00000477056.1
ENSG00000241489	ENST00000441880.1	n.*18C>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111468 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000166 AC: 3 AN: 180824 AF XY: 0.0000458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000371

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000640 AC: 7 AN: 1093634 Hom.: 0 Cov.: 30 AF XY: 0.00000834 AC XY: 3 AN XY: 359886

African (AFR) AF: 0.00 AC: 0 AN: 26287

American (AMR) AF: 0.00 AC: 0 AN: 35059

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19209

East Asian (EAS) AF: 0.00 AC: 0 AN: 30111

South Asian (SAS) AF: 0.00 AC: 0 AN: 53828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00000835 AC: 7 AN: 838697

Other (OTH) AF: 0.00 AC: 0 AN: 45887

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111468 Hom.: 0 Cov.: 22 AF XY: 0.0000297 AC XY: 1 AN XY: 33662

African (AFR) AF: 0.00 AC: 0 AN: 30627

American (AMR) AF: 0.00 AC: 0 AN: 10482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2655

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53086

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Benign:1

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.5
DANN	Benign	0.79
PhyloP100		0.56
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: rs199422227; hg19: chrX-148564603;