rs145231211

Variant names:

• chrX-149500989-G-T
• rs145231211
• NM_000202.8:c.467C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000202.8(IDS):​c.467C>A​(p.Pro156Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,179,632 control chromosomes in the GnomAD database, including 10 homozygotes. There are 429 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (8 hom., 231 hem., cov: 23)
  • Exomes 𝑓: 0.00069 (2 hom. 198 hem.)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 4.08
• Publications: 1 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 -18 ACMG points.

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_000202.8
• BP4: Computational evidence support a benign effect (MetaRNN=0.016393512).
• BP6: Variant X-149500989-G-T is Benign according to our data. Variant chrX-149500989-G-T is described in ClinVar as Benign. ClinVar VariationId is 457346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00763 (848/111115) while in subpopulation AFR AF = 0.0264 (805/30457). AF 95% confidence interval is 0.0249. There are 8 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.467C>A	p.Pro156Gln	missense	Exon 4 of 9	NP_000193.1	P22304-1
	IDS	NM_001166550.4		c.197C>A	p.Pro66Gln	missense	Exon 4 of 9	NP_001160022.1	B4DGD7
	IDS	NM_006123.5		c.467C>A	p.Pro156Gln	missense	Exon 4 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.467C>A	p.Pro156Gln	missense	Exon 4 of 9	ENSP00000339801.6	P22304-1
	IDS	ENST00000370441.8	TSL:1	c.467C>A	p.Pro156Gln	missense	Exon 4 of 8	ENSP00000359470.4	P22304-2
	ENSG00000241489	ENST00000651111.1		c.-167C>A		5_prime_UTR	Exon 9 of 14	ENSP00000498395.1	B3KWA1

Frequencies

GnomAD3 genomes AF: 0.00761 AC: 845 AN: 111065 Hom.: 8 Cov.: 23

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00258

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: 0.0000944

Gnomad OTH AF: 0.00733

GnomAD2 exomes AF: 0.00225 AC: 413 AN: 183371 AF XY: 0.00145

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000732

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000694 AC: 742 AN: 1068517 Hom.: 2 Cov.: 26 AF XY: 0.000585 AC XY: 198 AN XY: 338725

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

African (AFR) AF: 0.0240 AC: 616 AN: 25681

American (AMR) AF: 0.00114 AC: 40 AN: 35185

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19212

East Asian (EAS) AF: 0.00 AC: 0 AN: 30142

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40436

Middle Eastern (MID) AF: 0.00123 AC: 5 AN: 4067

European-Non Finnish (NFE) AF: 0.0000270 AC: 22 AN: 814870

Other (OTH) AF: 0.00128 AC: 58 AN: 45196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00763 AC: 848 AN: 111115 Hom.: 8 Cov.: 23 AF XY: 0.00692 AC XY: 231 AN XY: 33363

African (AFR) AF: 0.0264 AC: 805 AN: 30457

American (AMR) AF: 0.00258 AC: 27 AN: 10480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.00 AC: 0 AN: 2636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000944 AC: 5 AN: 52973

Other (OTH) AF: 0.00724 AC: 11 AN: 1520

Alfa AF: 0.00147 Hom.: 68

Bravo AF: 0.00910

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0318 AC: 122

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00265 AC: 322

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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	0.084
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.012	D
Sift4G	Benign	0.12	T
Polyphen		0.49	P
Vest4		0.52
MVP		0.93
MPC		2.1
ClinPred		0.093	T
GERP RS		3.6
Varity_R		0.62
gMVP		0.96
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs145231211; hg19: chrX-148582520; COSMIC: COSV107432993; COSMIC: COSV107432993;