rs3755956

Variant names:

• chr4-1000568-C-T
• rs3755956
• NM_000203.5:c.300-44C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000203.5(IDUA):​c.300-44C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,451,130 control chromosomes in the GnomAD database, including 1,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (125 hom., cov: 34)
  • Exomes 𝑓: 0.039 (1220 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.77
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-1000568-C-T is Benign according to our data. Variant chr4-1000568-C-T is described in ClinVar as Benign. ClinVar VariationId is 255526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

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.300-44C>T		intron	N/A	NP_000194.2
	IDUA	NM_001363576.1		c.-97-44C>T		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.388-44C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.300-44C>T		intron	N/A	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.300-44C>T		intron	N/A	ENSP00000247933.4
	IDUA	ENST00000962389.1		c.375-44C>T		intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4915 AN: 152238 Hom.: 124 Cov.: 34

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0507

GnomAD2 exomes AF: 0.0372 AC: 9248 AN: 248650 AF XY: 0.0361

Gnomad AFR exome AF: 0.00949

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.0516

Gnomad NFE exome AF: 0.0385

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0385 AC: 50030 AN: 1298774 Hom.: 1220 Cov.: 19 AF XY: 0.0376 AC XY: 24643 AN XY: 654688

African (AFR) AF: 0.00954 AC: 290 AN: 30390

American (AMR) AF: 0.0209 AC: 930 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 345 AN: 25154

East Asian (EAS) AF: 0.114 AC: 4442 AN: 38926

South Asian (SAS) AF: 0.0137 AC: 1133 AN: 82886

European-Finnish (FIN) AF: 0.0531 AC: 2765 AN: 52034

Middle Eastern (MID) AF: 0.0259 AC: 141 AN: 5450

European-Non Finnish (NFE) AF: 0.0392 AC: 37758 AN: 964318

Other (OTH) AF: 0.0404 AC: 2226 AN: 55100

GnomAD4 genome AF: 0.0323 AC: 4919 AN: 152356 Hom.: 125 Cov.: 34 AF XY: 0.0327 AC XY: 2433 AN XY: 74508

African (AFR) AF: 0.0109 AC: 454 AN: 41580

American (AMR) AF: 0.0327 AC: 500 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.119 AC: 617 AN: 5188

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4832

European-Finnish (FIN) AF: 0.0490 AC: 520 AN: 10620

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0377 AC: 2562 AN: 68036

Other (OTH) AF: 0.0544 AC: 115 AN: 2114

Alfa AF: 0.0313 Hom.: 14

Bravo AF: 0.0315

Asia WGS AF: 0.0730 AC: 254 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.42
DANN	Benign	0.53
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs3755956; hg19: chr4-994356; COSMIC: COSV56104596; COSMIC: COSV56104596;