4-1002713-GCCC-GCCCCC

Variant names:

• chr4-1002713-G-GCC
• rs150523349
• NM_000203.5:c.1190-11_1190-10dupCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000203.5(IDUA):​c.1190-11_1190-10dupCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,363,574 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 29)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 4-1002713-G-GCC is Benign according to our data. Variant chr4-1002713-G-GCC is described in ClinVar as Benign. ClinVar VariationId is 1600766.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00128 (192/149760) while in subpopulation AFR AF = 0.00373 (152/40706). AF 95% confidence interval is 0.00325. There are 2 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1190-11_1190-10dupCC		intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.794-11_794-10dupCC		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1278-11_1278-10dupCC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1190-19_1190-18insCC		intron	N/A	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1190-19_1190-18insCC		intron	N/A	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1265-19_1265-18insCC		intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 193 AN: 149662 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000396

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000595

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00654

Gnomad NFE AF: 0.000342

Gnomad OTH AF: 0.000978

GnomAD2 exomes AF: 0.000738 AC: 54 AN: 73188 AF XY: 0.000916

Gnomad AFR exome AF: 0.00188

Gnomad AMR exome AF: 0.000133

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.00192

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.000452

Gnomad OTH exome AF: 0.000908

GnomAD4 exome AF: 0.000302 AC: 366 AN: 1213814 Hom.: 0 Cov.: 24 AF XY: 0.000333 AC XY: 200 AN XY: 601188

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

African (AFR) AF: 0.00112 AC: 27 AN: 24082

American (AMR) AF: 0.000172 AC: 5 AN: 29050

Ashkenazi Jewish (ASJ) AF: 0.000312 AC: 7 AN: 22404

East Asian (EAS) AF: 0.000173 AC: 5 AN: 28868

South Asian (SAS) AF: 0.00186 AC: 125 AN: 67350

European-Finnish (FIN) AF: 0.000122 AC: 4 AN: 32706

Middle Eastern (MID) AF: 0.000554 AC: 2 AN: 3610

European-Non Finnish (NFE) AF: 0.000180 AC: 172 AN: 954808

Other (OTH) AF: 0.000373 AC: 19 AN: 50936

⚠️ 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: 0.00128 AC: 192 AN: 149760 Hom.: 2 Cov.: 29 AF XY: 0.00123 AC XY: 90 AN XY: 73090

African (AFR) AF: 0.00373 AC: 152 AN: 40706

American (AMR) AF: 0.000396 AC: 6 AN: 15158

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

East Asian (EAS) AF: 0.000596 AC: 3 AN: 5030

South Asian (SAS) AF: 0.00106 AC: 5 AN: 4716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10260

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.000342 AC: 23 AN: 67198

Other (OTH) AF: 0.000967 AC: 2 AN: 2068

Alfa AF: 0.000864 Hom.: 107

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Mucopolysaccharidosis type 1 (1)

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;