rs387906504

Positions:

• chr4-1004391-T-C
• chr4-1004391-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_000203.5(IDUA):​c.1960T>C​(p.Ter654Argext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDUA NM_000203.5 stop_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 0.123

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]

IDUA (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000203.5 Downstream stopcodon found after 666 codons.
• PP5: Variant 4-1004391-T-C is Pathogenic according to our data. Variant chr4-1004391-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 960079.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1960T>C	p.Ter654Argext*?	stop_lost	14/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1960T>C	p.Ter654Argext*?	stop_lost	14/14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1960T>C	p.Ter654Argext*?	stop_lost	14/14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.2071T>C		non_coding_transcript_exon_variant	11/11	5
IDUA	ENST00000652070.1	n.2016T>C		non_coding_transcript_exon_variant	13/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 30, 2019	This sequence change disrupts the translational stop signal of the IDUA mRNA. It is expected to extend the length of the IDUA protein by 55 additional amino acid residues. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect IDUA protein function (PMID: 29282708). This variant has been observed in several individuals affected with IDUA-related conditions (PMID: 21394825, 29282708). -
not provided, no classification provided	literature only	GeneReviews	-	Variant causes attenuated MPS I; predict extension of α-L-iduronidase at the carboxyl end that may change conformation and/or stability of enzyme. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.4
DANN	Benign	0.58
Eigen	Benign	0.055
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.012	N
Vest4		0.15
GERP RS		-0.75

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: rs387906504; hg19: chr4-998179;