chr4-1002009-G-C

Variant names:

• chr4-1002009-G-C
• rs1553917192
• NM_000203.5:c.820G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000203.5(IDUA):​c.820G>C​(p.Glu274Gln) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E274E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51
• 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: 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000203.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.820G>C	p.Glu274Gln	missense_variant	Exon 7 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.424G>C	p.Glu142Gln	missense_variant	Exon 6 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.820G>C	p.Glu274Gln	missense_variant	Exon 7 of 12		XP_047271606.1
IDUA	NR_110313.1	n.908G>C		non_coding_transcript_exon_variant	Exon 7 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.820G>C	p.Glu274Gln	missense_variant	Exon 7 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0023	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Uncertain	0.59	D;D;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.75	T;.;.
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	0.025	D
MutationAssessor	Benign	1.6	L;.;.
PhyloP100		2.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.72	N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.56	P;.;.
Vest4		0.14
MutPred		0.53		Gain of glycosylation at S269 (P = 0.0185);.;.;
MVP		0.98
MPC		0.75
ClinPred		0.44	T
GERP RS		4.1
Varity_R		0.34
gMVP		0.78
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: 3

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

Other links and lift over

dbSNP: rs1553917192; hg19: chr4-995797;