X-149500991-A-T

Variant names:

• chrX-149500991-A-T
• rs149210251
• NM_000202.8:c.465T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 6P and 20B. PS1 PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000202.8(IDS):​c.465T>A​(p.Phe155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,183,684 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F155F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (8 hom., 231 hem., cov: 24)
  • Exomes 𝑓: 0.00069 (2 hom. 198 hem.)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.117
• 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 -14 ACMG points.

• PS1: Transcript NM_000202.8 (IDS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in NM_000202.8
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029900074).
• BP6: Variant X-149500991-A-T is Benign according to our data. Variant chrX-149500991-A-T is described in ClinVar as Benign. ClinVar VariationId is 457354.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 = 0.0076 (848/111555) while in subpopulation AFR AF = 0.0263 (805/30590). AF 95% confidence interval is 0.0248. There are 8 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 24. 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.465T>A	p.Phe155Leu	missense	Exon 4 of 9	NP_000193.1	P22304-1
	IDS	NM_001166550.4		c.195T>A	p.Phe65Leu	missense	Exon 4 of 9	NP_001160022.1	B4DGD7
	IDS	NM_006123.5		c.465T>A	p.Phe155Leu	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.465T>A	p.Phe155Leu	missense	Exon 4 of 9	ENSP00000339801.6	P22304-1
	IDS	ENST00000370441.8	TSL:1	c.465T>A	p.Phe155Leu	missense	Exon 4 of 8	ENSP00000359470.4	P22304-2
	ENSG00000241489	ENST00000651111.1		c.-169T>A		5_prime_UTR	Exon 9 of 14	ENSP00000498395.1	B3KWA1

Frequencies

GnomAD3 genomes AF: 0.00758 AC: 845 AN: 111502 Hom.: 8 Cov.: 24

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

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: 0.0000942

Gnomad OTH AF: 0.00731

GnomAD2 exomes AF: 0.00225 AC: 413 AN: 183380 AF XY: 0.00144

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: 0.000693 AC: 743 AN: 1072129 Hom.: 2 Cov.: 26 AF XY: 0.000579 AC XY: 198 AN XY: 341811

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

African (AFR) AF: 0.0240 AC: 618 AN: 25752

American (AMR) AF: 0.00111 AC: 39 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19241

East Asian (EAS) AF: 0.00 AC: 0 AN: 30157

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40462

Middle Eastern (MID) AF: 0.00122 AC: 5 AN: 4084

European-Non Finnish (NFE) AF: 0.0000269 AC: 22 AN: 818165

Other (OTH) AF: 0.00128 AC: 58 AN: 45285

⚠️ 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: 0.00760 AC: 848 AN: 111555 Hom.: 8 Cov.: 24 AF XY: 0.00684 AC XY: 231 AN XY: 33753

African (AFR) AF: 0.0263 AC: 805 AN: 30590

American (AMR) AF: 0.00256 AC: 27 AN: 10544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000942 AC: 5 AN: 53055

Other (OTH) AF: 0.00722 AC: 11 AN: 1524

Alfa AF: 0.000599 Hom.: 16

Bravo AF: 0.00910

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0310 AC: 119

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
-	-	3	not provided (3)
-	-	1	IDS-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Mucopolysaccharidosis, MPS-II (1)
-	-	1	Mucopolysaccharidosis, MPS-III-A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	5.8
DANN	Benign	0.80
DEOGEN2	Uncertain	0.60	D
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0030	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	-0.97	N
PhyloP100		0.12
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.27	N
REVEL	Uncertain	0.33
Sift	Benign	0.70	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.45		Gain of helix (P = 0.0425)
MVP		0.49
MPC		1.2
ClinPred		0.0036	T
GERP RS		-3.9
Varity_R		0.18
gMVP		0.88
Mutation Taster		=297/3	polymorphism (auto)

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: rs149210251; hg19: chrX-148582522; COSMIC: COSV107432994; COSMIC: COSV107432994;