rs1553917192

chr4-1002009-G-Cchr4-1002009-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. 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

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.820G>C	p.Glu274Gln	missense_variant	7/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.820G>C	p.Glu274Gln	missense_variant	7/14	2	NM_000203.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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;.;.
MutationTaster	Benign	0.95	D;D;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553917192; hg19: chr4-995797;