X-149496444-G-T

Variant names:

• chrX-149496444-G-T
• rs141720810
• NM_000202.8:c.781C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1 BP4_Moderate BP6_Moderate BS1 BS2

The NM_000202.8(IDS):​c.781C>A​(p.Pro261Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,095,325 control chromosomes in the GnomAD database, including 1 homozygotes. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P261A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000016 (1 hom. 5 hem.)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0170
• Publications: 3 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.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000202.8
• BP4: Computational evidence support a benign effect (MetaRNN=0.2224598).
• BP6: Variant X-149496444-G-T is Benign according to our data. Variant chrX-149496444-G-T is described in ClinVar as Benign. ClinVar VariationId is 1170676.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000164 (18/1095325) while in subpopulation SAS AF = 0.000222 (12/54071). AF 95% confidence interval is 0.000128. There are 1 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000202.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	NM_000202.8	MANE Select	c.781C>A	p.Pro261Thr	missense	Exon 6 of 9	NP_000193.1
	IDS	NM_001166550.4		c.511C>A	p.Pro171Thr	missense	Exon 6 of 9	NP_001160022.1
	IDS	NM_006123.5		c.781C>A	p.Pro261Thr	missense	Exon 6 of 8	NP_006114.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	ENST00000340855.11	TSL:1 MANE Select	c.781C>A	p.Pro261Thr	missense	Exon 6 of 9	ENSP00000339801.6
	IDS	ENST00000370441.8	TSL:1	c.781C>A	p.Pro261Thr	missense	Exon 6 of 8	ENSP00000359470.4
	ENSG00000241489	ENST00000651111.1		c.148C>A	p.Pro50Thr	missense	Exon 11 of 14	ENSP00000498395.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000601 AC: 11 AN: 183076 AF XY: 0.0000444

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1095325 Hom.: 1 Cov.: 30 AF XY: 0.0000139 AC XY: 5 AN XY: 360805

African (AFR) AF: 0.00 AC: 0 AN: 26353

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.000222 AC: 12 AN: 54071

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3978

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 839662

Other (OTH) AF: 0.0000870 AC: 4 AN: 45964

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000359 Hom.: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Mucopolysaccharidosis, MPS-II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	9.4
DANN	Benign	0.82
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.22	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.64	N
PhyloP100		-0.017
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.41
Sift	Benign	0.97	T
Sift4G	Benign	0.78	T
Polyphen		0.0030	B
Vest4		0.22
MutPred		0.51		Loss of catalytic residue at P260 (P = 0.0121)
MVP		0.79
MPC		0.23
ClinPred		0.051	T
GERP RS		2.8
Varity_R		0.25
gMVP		0.69
Mutation Taster		=93/7	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: rs141720810; hg19: chrX-148577975;