rs368513342

chrX-149504161-G-AchrX-149504161-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM5 PP3_Moderate

The NM_000202.8(IDS):c.236C>T(p.Ala79Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000064 in 1,093,191 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.15

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000202.8
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDS	NM_000202.8	c.236C>T	p.Ala79Val	missense_variant	2/9	ENST00000340855.11
IDS	NM_001166550.4	c.10C>T	p.Arg4Cys	missense_variant	2/9
IDS	NM_006123.5	c.236C>T	p.Ala79Val	missense_variant	2/8
IDS	NR_104128.2	n.405C>T		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.236C>T	p.Ala79Val	missense_variant	2/9	1	NM_000202.8	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000115 AC: 2 AN: 173948 Hom.: 0 AF XY: 0.0000168 AC XY: 1 AN XY: 59520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000374

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000566

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000640 AC: 7 AN: 1093191 Hom.: 0 Cov.: 29 AF XY: 0.00000836 AC XY: 3 AN XY: 358971

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000286

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000562

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000358

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2017

The p.A79V variant (also known as c.236C>T), located in coding exon 2 of the IDS gene, results from a C to T substitution at nucleotide position 236. The alanine at codon 79 is replaced by valine, an amino acid with similar properties. Another alteration at this position has been reported in the literature in an individual with mild symptoms of Hunter syndrome (Karsten S et al. Hum. Genet. 1998 Dec;103(6):732-5). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Mucopolysaccharidosis, MPS-III-A Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Mucopolysaccharidosis, MPS-II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;D;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.47	N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.44	T;T;T;.
Polyphen		0.54	P;P;B;.
Vest4		0.38
MutPred		0.83		Loss of catalytic residue at A79 (P = 0.1487);Loss of catalytic residue at A79 (P = 0.1487);Loss of catalytic residue at A79 (P = 0.1487);Loss of catalytic residue at A79 (P = 0.1487);
MVP		0.97
MPC		1.7
ClinPred		0.52	D
GERP RS		4.0
Varity_R		0.44
gMVP		0.97

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: rs368513342; hg19: chrX-148585691;