chr4-1002980-T-C

Variant names:

• chr4-1002980-T-C
• rs115134980
• NM_000203.5:c.1402+36T>C

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.1402+36T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,392,176 control chromosomes in the GnomAD database, including 19,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2402 hom., cov: 33)
  • Exomes 𝑓: 0.16 (17050 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.42
• Publications: 10 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=-0.89).
• BP6: Variant 4-1002980-T-C is Benign according to our data. Variant chr4-1002980-T-C is described in ClinVar as Benign. ClinVar VariationId is 255522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.288 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.1402+36T>C		intron	N/A	NP_000194.2
	IDUA	NM_001363576.1		c.1006+36T>C		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1490+36T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1402+36T>C		intron	N/A	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1402+36T>C		intron	N/A	ENSP00000247933.4
	IDUA	ENST00000502829.1	TSL:2	n.204+36T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26500 AN: 151524 Hom.: 2406 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.157 AC: 5479 AN: 34990 AF XY: 0.169

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.0620

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.196

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.160 AC: 199015 AN: 1240546 Hom.: 17050 Cov.: 36 AF XY: 0.163 AC XY: 98716 AN XY: 605004

African (AFR) AF: 0.220 AC: 5436 AN: 24710

American (AMR) AF: 0.0888 AC: 1316 AN: 14828

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 2973 AN: 18962

East Asian (EAS) AF: 0.157 AC: 4352 AN: 27658

South Asian (SAS) AF: 0.291 AC: 16925 AN: 58144

European-Finnish (FIN) AF: 0.175 AC: 5330 AN: 30434

Middle Eastern (MID) AF: 0.201 AC: 961 AN: 4790

European-Non Finnish (NFE) AF: 0.152 AC: 153171 AN: 1009998

Other (OTH) AF: 0.168 AC: 8551 AN: 51022

GnomAD4 genome AF: 0.175 AC: 26496 AN: 151630 Hom.: 2402 Cov.: 33 AF XY: 0.176 AC XY: 13040 AN XY: 74122

African (AFR) AF: 0.213 AC: 8806 AN: 41372

American (AMR) AF: 0.124 AC: 1888 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3464

East Asian (EAS) AF: 0.200 AC: 1020 AN: 5098

South Asian (SAS) AF: 0.301 AC: 1445 AN: 4798

European-Finnish (FIN) AF: 0.165 AC: 1737 AN: 10516

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.154 AC: 10413 AN: 67794

Other (OTH) AF: 0.184 AC: 388 AN: 2110

Alfa AF: 0.146 Hom.: 219

Bravo AF: 0.170

Asia WGS AF: 0.251 AC: 867 AN: 3442

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucopolysaccharidosis, MPS-I-H/S Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucopolysaccharidosis, MPS-I-S Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucopolysaccharidosis type 1 Benign:1

Apr 13, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hurler syndrome Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.2
DANN	Benign	0.11
PhyloP100		-3.4
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: rs115134980; hg19: chr4-996768; COSMIC: COSV56105910; COSMIC: COSV56105910;