4-1004275-CTG-C

Position:

• chr4-1004275-CTG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000203.5(IDUA):​c.1845_1846del​(p.Gly616LeufsTer42) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDUA NM_000203.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.89

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-1004275-CTG-C is Pathogenic according to our data. Variant chr4-1004275-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556253.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1845_1846del	p.Gly616LeufsTer42	frameshift_variant	14/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1845_1846del	p.Gly616LeufsTer42	frameshift_variant	14/14	2	NM_000203.5	ENSP00000425081	P1
IDUA	ENST00000247933.9	c.1845_1846del	p.Gly616LeufsTer42	frameshift_variant	14/14	1		ENSP00000247933	P1
IDUA	ENST00000514698.5	n.1956_1957del		non_coding_transcript_exon_variant	11/11	5
IDUA	ENST00000652070.1	n.1901_1902del		non_coding_transcript_exon_variant	13/13

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hurler syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jan 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553917737; hg19: chr4-998063;