4-1003402-C-T

Variant names:

• chr4-1003402-C-T
• rs199722340
• NM_000203.5:c.1582C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000203.5(IDUA):​c.1582C>T​(p.Pro528Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,372,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P528A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.265
• Publications: 0 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: Myriad Women’s Health, ClinGen
• Scheie syndrome

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

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

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000203.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15304935).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1582C>T	p.Pro528Ser	missense	Exon 11 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1186C>T	p.Pro396Ser	missense	Exon 10 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1670C>T		non_coding_transcript_exon	Exon 11 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1582C>T	p.Pro528Ser	missense	Exon 11 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1582C>T	p.Pro528Ser	missense	Exon 11 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1657C>T	p.Pro553Ser	missense	Exon 12 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1372834 Hom.: 0 Cov.: 33 AF XY: 0.00000148 AC XY: 1 AN XY: 677230

African (AFR) AF: 0.00 AC: 0 AN: 30188

American (AMR) AF: 0.0000285 AC: 1 AN: 35042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24732

East Asian (EAS) AF: 0.00 AC: 0 AN: 34740

South Asian (SAS) AF: 0.00 AC: 0 AN: 78236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074988

Other (OTH) AF: 0.00 AC: 0 AN: 57256

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	5.1
DANN	Benign	0.86
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.27
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.12
Sift	Benign	0.74	T
Sift4G	Benign	0.74	T
Polyphen		0.053	B
Vest4		0.081
MVP		0.76
MPC		0.50
ClinPred		0.10	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.65
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs199722340; hg19: chr4-997190;