chrX-149482795-A-T

Variant names:

• chrX-149482795-A-T
• rs782166680
• NM_000202.8:c.1604T>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BS1 BS2

The NM_000202.8(IDS):​c.1604T>A​(p.Met535Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,257 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 3 hem.)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.95

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]

ENSG00000241489 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a chain Iduronate 2-sulfatase 14 kDa chain (size 94) in uniprot entity IDS_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000202.8
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00000546 (6/1098257) while in subpopulation SAS AF= 0.000111 (6/54149). AF 95% confidence interval is 0.0000477. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.1604T>A	p.Met535Lys	missense_variant	Exon 9 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.1334T>A	p.Met445Lys	missense_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.1604T>A	p.Met535Lys	missense_variant	Exon 9 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.971T>A	p.Met324Lys	missense_variant	Exon 14 of 14			ENSP00000498395.1
ENSG00000241489	ENST00000422081.6	c.971T>A	p.Met324Lys	missense_variant	Exon 9 of 9	2		ENSP00000477056.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000218 AC: 4 AN: 183192 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67672

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 SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1098257 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 3 AN XY: 363611

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.70	D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.047	B;.
Vest4		0.34
MutPred		0.59		Loss of loop (P = 0.0022);.;
MVP		0.91
MPC		0.34
ClinPred		0.41	T
GERP RS		5.8
Varity_R		0.91
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs782166680; hg19: chrX-148564326;