rs121965028

Variant names:

• chr4-1004389-CATG-C
• rs121965028
• NM_000203.5:c.1960_1962delTGA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000203.5(IDUA):​c.1960_1962delTGA​(p.Ter654del) variant causes a stop lost, conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene IDUA is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDUA NM_000203.5 stop_lost, conservative_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.82
• 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

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000203.5 Downstream stopcodon found after 666 codons.

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.1960_1962delTGA	p.Ter654del	stop_lost conservative_inframe_deletion	Exon 14 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1564_1566delTGA	p.Ter522del	stop_lost conservative_inframe_deletion	Exon 13 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.2052_2054delTGA		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1960_1962delTGA	p.Ter654del	stop_lost conservative_inframe_deletion	Exon 14 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1960_1962delTGA	p.Ter654del	stop_lost conservative_inframe_deletion	Exon 14 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.2035_2037delTGA	p.Ter679del	stop_lost conservative_inframe_deletion	Exon 15 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8

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: rs121965028; hg19: chr4-998177;