4-1002713-GCCCC-GCCCCCCCCCC

Variant names:

• chr4-1002713-G-GCCCCCC
• rs150523349
• NM_000203.5:c.1190-15_1190-10dupCCCCCC

Variant summary

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

The NM_000203.5(IDUA):​c.1190-15_1190-10dupCCCCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000044 in 1,364,562 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: 𝑓 0.000020 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000025 (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: 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1190-15_1190-10dupCCCCCC		intron	N/A	NP_000194.2
	IDUA	NM_001363576.1		c.794-15_794-10dupCCCCCC		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1278-15_1278-10dupCCCCCC		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1190-15_1190-10dupCCCCCC		intron	N/A	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1190-15_1190-10dupCCCCCC		intron	N/A	ENSP00000247933.4
	IDUA	ENST00000514698.5	TSL:5	n.1297-15_1297-10dupCCCCCC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 149678 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000547 AC: 4 AN: 73188 AF XY: 0.0000723

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000377

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000247 AC: 3 AN: 1214884 Hom.: 0 Cov.: 24 AF XY: 0.00000332 AC XY: 2 AN XY: 601830

⚠️ 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: 24130

American (AMR) AF: 0.00 AC: 0 AN: 29058

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

East Asian (EAS) AF: 0.0000346 AC: 1 AN: 28878

South Asian (SAS) AF: 0.0000148 AC: 1 AN: 67644

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: 955412

Other (OTH) AF: 0.00 AC: 0 AN: 50970

⚠️ 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 AF: 0.0000200 AC: 3 AN: 149678 Hom.: 0 Cov.: 29 AF XY: 0.0000137 AC XY: 1 AN XY: 72992

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

African (AFR) AF: 0.0000246 AC: 1 AN: 40604

American (AMR) AF: 0.0000661 AC: 1 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5046

South Asian (SAS) AF: 0.00 AC: 0 AN: 4726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67210

Other (OTH) AF: 0.00 AC: 0 AN: 2046

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000647710), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.79

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs150523349; hg19: chr4-996501;