4-1002713-GCCCC-GCCC

Variant names:

• chr4-1002713-GC-G
• rs150523349
• NM_000203.5:c.1190-10delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000203.5(IDUA):​c.1190-10delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,358,110 control chromosomes in the GnomAD database, including 112 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (51 hom., cov: 29)
  • Exomes 𝑓: 0.0025 (61 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 -16 ACMG points.

• BP6: Variant 4-1002713-GC-G is Benign according to our data. Variant chr4-1002713-GC-G is described in ClinVar as Benign. ClinVar VariationId is 496833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0151 (2265/149774) while in subpopulation AFR AF = 0.0494 (2012/40716). AF 95% confidence interval is 0.0476. There are 51 homozygotes in GnomAd4. There are 1056 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 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.1190-10delC		intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.794-10delC		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1278-10delC		intron	N/A

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2254 AN: 149676 Hom.: 49 Cov.: 29

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00971

Gnomad ASJ AF: 0.00930

Gnomad EAS AF: 0.00119

Gnomad SAS AF: 0.000635

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.000595

Gnomad OTH AF: 0.0122

GnomAD2 exomes AF: 0.00548 AC: 401 AN: 73188 AF XY: 0.00417

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00808

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00741

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00954

GnomAD4 exome AF: 0.00253 AC: 3062 AN: 1208336 Hom.: 61 Cov.: 24 AF XY: 0.00221 AC XY: 1322 AN XY: 598660

African (AFR) AF: 0.0486 AC: 1166 AN: 24008

American (AMR) AF: 0.00654 AC: 188 AN: 28732

Ashkenazi Jewish (ASJ) AF: 0.00812 AC: 181 AN: 22302

East Asian (EAS) AF: 0.00226 AC: 65 AN: 28798

South Asian (SAS) AF: 0.000787 AC: 53 AN: 67310

European-Finnish (FIN) AF: 0.000184 AC: 6 AN: 32680

Middle Eastern (MID) AF: 0.00554 AC: 20 AN: 3610

European-Non Finnish (NFE) AF: 0.00113 AC: 1078 AN: 950188

Other (OTH) AF: 0.00601 AC: 305 AN: 50708

GnomAD4 genome AF: 0.0151 AC: 2265 AN: 149774 Hom.: 51 Cov.: 29 AF XY: 0.0144 AC XY: 1056 AN XY: 73100

African (AFR) AF: 0.0494 AC: 2012 AN: 40716

American (AMR) AF: 0.00970 AC: 147 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00930 AC: 32 AN: 3442

East Asian (EAS) AF: 0.00119 AC: 6 AN: 5030

South Asian (SAS) AF: 0.000424 AC: 2 AN: 4716

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

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

European-Non Finnish (NFE) AF: 0.000595 AC: 40 AN: 67200

Other (OTH) AF: 0.0121 AC: 25 AN: 2068

Alfa AF: 0.00508 Hom.: 107

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Mucopolysaccharidosis type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism

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: rs150523349; hg19: chr4-996501; COSMIC: COSV56102345; COSMIC: COSV56102345;