rs121965025

Variant names:

• chr4-1004292-C-A
• rs121965025
• NM_000203.5:c.1861C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1004292-C-A
• chr4-1004292-C-G
• chr4-1004292-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_000203.5(IDUA):​c.1861C>A​(p.Arg621Arg) variant causes a synonymous 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 Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. R621R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDUA NM_000203.5 synonymous
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.51
• Publications: 23 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_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP7: Synonymous conserved (PhyloP=1.51 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1861C>A	p.Arg621Arg	synonymous_variant	Exon 14 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.1465C>A	p.Arg489Arg	synonymous_variant	Exon 13 of 13		NP_001350505.1
IDUA	NR_110313.1	n.1953C>A		non_coding_transcript_exon_variant	Exon 14 of 14
IDUA	XM_047415650.1	c.*300C>A		downstream_gene_variant			XP_047271606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1861C>A	p.Arg621Arg	synonymous_variant	Exon 14 of 14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1861C>A	p.Arg621Arg	synonymous_variant	Exon 14 of 14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1972C>A		non_coding_transcript_exon_variant	Exon 11 of 11	5
IDUA	ENST00000652070.1	n.1917C>A		non_coding_transcript_exon_variant	Exon 13 of 13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Mucopolysaccharidosis type 1 Uncertain:1

Mar 23, 2025

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121965025; hg19: chr4-998080;