chr4-1003198-G-T

Variant names:

• chr4-1003198-G-T
• rs188458034
• NM_000203.5:c.1524+41G>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.1524+41G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,300,228 control chromosomes in the GnomAD database, including 12,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1756 hom., cov: 30)
  • Exomes 𝑓: 0.13 (10675 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.666
• Publications: 2 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=-0.81).
• BP6: Variant 4-1003198-G-T is Benign according to our data. Variant chr4-1003198-G-T is described in ClinVar as Benign. ClinVar VariationId is 255524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 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.1524+41G>T		intron	N/A	NP_000194.2
	IDUA	NM_001363576.1		c.1128+41G>T		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1612+41G>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.1524+41G>T		intron	N/A	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1524+41G>T		intron	N/A	ENSP00000247933.4
	IDUA	ENST00000502829.1	TSL:2	n.367G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22481 AN: 150816 Hom.: 1762 Cov.: 30

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.159

GnomAD2 exomes AF: 0.152 AC: 88 AN: 580 AF XY: 0.172

Gnomad AFR exome AF: 0.0909

Gnomad AMR exome AF: 0.0192

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.132 AC: 151354 AN: 1149304 Hom.: 10675 Cov.: 31 AF XY: 0.132 AC XY: 73147 AN XY: 552692

African (AFR) AF: 0.192 AC: 4363 AN: 22694

American (AMR) AF: 0.0945 AC: 791 AN: 8372

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 2141 AN: 15208

East Asian (EAS) AF: 0.135 AC: 3510 AN: 25984

South Asian (SAS) AF: 0.214 AC: 8329 AN: 38876

European-Finnish (FIN) AF: 0.139 AC: 3701 AN: 26702

Middle Eastern (MID) AF: 0.198 AC: 623 AN: 3150

European-Non Finnish (NFE) AF: 0.126 AC: 121374 AN: 961464

Other (OTH) AF: 0.139 AC: 6522 AN: 46854

GnomAD4 genome AF: 0.149 AC: 22472 AN: 150924 Hom.: 1756 Cov.: 30 AF XY: 0.149 AC XY: 10971 AN XY: 73788

African (AFR) AF: 0.181 AC: 7461 AN: 41112

American (AMR) AF: 0.112 AC: 1704 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 524 AN: 3448

East Asian (EAS) AF: 0.186 AC: 945 AN: 5080

South Asian (SAS) AF: 0.229 AC: 1097 AN: 4786

European-Finnish (FIN) AF: 0.128 AC: 1332 AN: 10408

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.131 AC: 8875 AN: 67572

Other (OTH) AF: 0.156 AC: 327 AN: 2098

Alfa AF: 0.130 Hom.: 119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.1
DANN	Benign	0.60
PhyloP100		-0.67
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: rs188458034; hg19: chr4-996986;