rs121965024

Variant names:

• chr4-1002392-A-C
• rs121965024
• NM_000203.5:c.1096A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000203.5(IDUA):​c.1096A>C​(p.Thr366Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.32
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000203.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847
• PP5: Variant 4-1002392-A-C is Pathogenic according to our data. Variant chr4-1002392-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 11916.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1096A>C	p.Thr366Pro	missense_variant	Exon 8 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.700A>C	p.Thr234Pro	missense_variant	Exon 7 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.1096A>C	p.Thr366Pro	missense_variant	Exon 8 of 12		XP_047271606.1
IDUA	NR_110313.1	n.1184A>C		non_coding_transcript_exon_variant	Exon 8 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1096A>C	p.Thr366Pro	missense_variant	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1096A>C	p.Thr366Pro	missense_variant	Exon 8 of 14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1203A>C		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1	n.1152A>C		non_coding_transcript_exon_variant	Exon 7 of 13

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Alfa AF: 0.000508 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hurler syndrome Pathogenic:1

Aug 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	23
DANN	Benign	0.84
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D;.
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.7	L;.
PhyloP100		4.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.83
Sift	Benign	0.14	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.053	B;.
Vest4		0.59
MVP		0.99
MPC		0.27
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.92
gMVP		0.83
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121965024; hg19: chr4-996180;