rs1557339927

chrX-149501038-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PP3_Strong PP5_Very_Strong

The NM_000202.8(IDS):c.419-1G>A variant causes a splice acceptor change. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IDS NM_000202.8 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.08

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 11, offset of 1, new splice context is: acctttttttttttccaaAGgat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-149501038-C-T is Pathogenic according to our data. Variant chrX-149501038-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 527324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149501038-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDS	NM_000202.8	c.419-1G>A		splice_acceptor_variant		ENST00000340855.11
IDS	NM_001166550.4	c.149-1G>A		splice_acceptor_variant
IDS	NM_006123.5	c.419-1G>A		splice_acceptor_variant
IDS	NR_104128.2	n.588-1G>A		splice_acceptor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.419-1G>A		splice_acceptor_variant		1	NM_000202.8	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1001973 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 292345

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 17, 2021	Variant summary: IDS c.419-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. Four predict the variant creates an adjacent alternative canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 181712 control chromosomes. To our knowledge, no occurrence of c.419-1G>A in individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic based on the identification of another splice variant, c.419-1G>C that has been reported in a patient with Mucopolysaccharidosis Type II (Hunter Syndrome). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2017	A different variant affecting this nucleotide (c.419-1G>C) has been determined to be pathogenic (PMID: 27351199). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IDS are known to be pathogenic (PMID: 8940265, 9875019). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with IDS-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 3 of the IDS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	34
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: -2
DS_AL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1557339927; hg19: chrX-148582569;