X-149496444-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_000202.8(IDS):​c.781C>G​(p.Pro261Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,207,511 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 51 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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. P261S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., 21 hem., cov: 23)
  • Exomes 𝑓: 0.000089 (0 hom. 30 hem.)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• 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 Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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 -9 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, 11 uncertain in NM_000202.8
• BP4: Computational evidence support a benign effect (MetaRNN=0.068737805).
• BP6: Variant X-149496444-G-C is Benign according to our data. Variant chrX-149496444-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 589455.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000606 (68/112186) while in subpopulation AFR AF = 0.00188 (58/30847). AF 95% confidence interval is 0.00149. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 21 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	NM_000202.8	MANE Select	c.781C>G	p.Pro261Ala	missense	Exon 6 of 9	NP_000193.1	P22304-1
	IDS	NM_001166550.4		c.511C>G	p.Pro171Ala	missense	Exon 6 of 9	NP_001160022.1	B4DGD7
	IDS	NM_006123.5		c.781C>G	p.Pro261Ala	missense	Exon 6 of 8	NP_006114.1	P22304-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	ENST00000340855.11	TSL:1 MANE Select	c.781C>G	p.Pro261Ala	missense	Exon 6 of 9	ENSP00000339801.6	P22304-1
	IDS	ENST00000370441.8	TSL:1	c.781C>G	p.Pro261Ala	missense	Exon 6 of 8	ENSP00000359470.4	P22304-2
	ENSG00000241489	ENST00000651111.1		c.148C>G	p.Pro50Ala	missense	Exon 11 of 14	ENSP00000498395.1	B3KWA1

Frequencies

GnomAD3 genomes AF: 0.000589 AC: 66 AN: 112132 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000940

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000268 AC: 49 AN: 183076 AF XY: 0.000192

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.000255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000895 AC: 98 AN: 1095325 Hom.: 0 Cov.: 30 AF XY: 0.0000831 AC XY: 30 AN XY: 360805

African (AFR) AF: 0.00182 AC: 48 AN: 26353

American (AMR) AF: 0.000142 AC: 5 AN: 35204

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

East Asian (EAS) AF: 0.000828 AC: 25 AN: 30193

South Asian (SAS) AF: 0.0000555 AC: 3 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: 0.00000119 AC: 1 AN: 839662

Other (OTH) AF: 0.000348 AC: 16 AN: 45964

GnomAD4 genome AF: 0.000606 AC: 68 AN: 112186 Hom.: 0 Cov.: 23 AF XY: 0.000611 AC XY: 21 AN XY: 34348

African (AFR) AF: 0.00188 AC: 58 AN: 30847

American (AMR) AF: 0.000939 AC: 10 AN: 10651

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.00 AC: 0 AN: 2699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53205

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000627

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Mucopolysaccharidosis, MPS-II (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Mucopolysaccharidosis, MPS-III-A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	8.9
DANN	Benign	0.71
DEOGEN2	Pathogenic	0.82	D
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.069	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.72	N
PhyloP100		-0.017
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.60
Sift	Benign	0.51	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.47
MVP		0.99
MPC		0.20
ClinPred		0.0032	T
GERP RS		2.8
Varity_R		0.12
gMVP		0.59
Mutation Taster		=87/13	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;