4-1002713-GCCCC-GC

Variant names:

• chr4-1002713-GCCC-G
• rs150523349
• NM_000203.5:c.1190-12_1190-10delCCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000203.5(IDUA):​c.1190-12_1190-10delCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000823 in 1,214,864 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792
• Publications: 3 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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1190-12_1190-10delCCC		intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.794-12_794-10delCCC		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1278-12_1278-10delCCC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1190-18_1190-16delCCC		intron	N/A	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1190-18_1190-16delCCC		intron	N/A	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1265-18_1265-16delCCC		intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.23e-7 AC: 1 AN: 1214864 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 601828

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24134

American (AMR) AF: 0.00 AC: 0 AN: 29060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22434

East Asian (EAS) AF: 0.00 AC: 0 AN: 28878

South Asian (SAS) AF: 0.00 AC: 0 AN: 67648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32742

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3616

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 955380

Other (OTH) AF: 0.00 AC: 0 AN: 50972

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.79

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: rs150523349; hg19: chr4-996501;