rs746766617

Positions:

• chr4-1002340-C-G
• chr4-1002340-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000203.5(IDUA):​c.1044C>G​(p.Asn348Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.0960

Genes affected

IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 4-1002340-C-G is Pathogenic according to our data. Variant chr4-1002340-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1044C>G	p.Asn348Lys	missense_variant	8/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1044C>G	p.Asn348Lys	missense_variant	8/14	2	NM_000203.5	ENSP00000425081	P1
IDUA	ENST00000247933.9	c.1044C>G	p.Asn348Lys	missense_variant	8/14	1		ENSP00000247933	P1
IDUA	ENST00000514698.5	n.1151C>G		non_coding_transcript_exon_variant	5/11	5
IDUA	ENST00000652070.1	n.1100C>G		non_coding_transcript_exon_variant	7/13

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248316 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134830

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460850 Hom.: 0 Cov.: 35 AF XY: 0.00000826 AC XY: 6 AN XY: 726718

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2022

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 348 of the IDUA protein (p.Asn348Lys). This variant is present in population databases (rs746766617, gnomAD 0.0009%). This missense change has been observed in individual(s) with IDUA-related conditions (PMID: 21394825, 23837464, 24875751). ClinVar contains an entry for this variant (Variation ID: 557870). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function. Experimental studies have shown that this missense change affects IDUA function (PMID: 24875751). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 03, 2021

- -

Hurler syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Apr 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Benign	0.13
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;.
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.093	T;T
Polyphen		0.99	D;.
Vest4		0.90
MVP		0.98
MPC		0.53
ClinPred		0.99	D
GERP RS		-1.6
Varity_R		0.87
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746766617; hg19: chr4-996128;