4-1002767-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000203.5(IDUA):c.1225G>C(p.Gly409Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,481,578 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G409E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (53 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 0.768

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030357838).
• BP6: Variant 4-1002767-G-C is Benign according to our data. Variant chr4-1002767-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92627.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=3, Uncertain_significance=1}. Variant chr4-1002767-G-C is described in Lovd as [Likely_benign]. Variant chr4-1002767-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.1225G>C	p.Gly409Arg	missense_variant	9/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.1225G>C	p.Gly409Arg	missense_variant	9/14	2	NM_000203.5	P1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2757 AN: 150922 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00924

Gnomad EAS AF: 0.0163

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.000487

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00358 AC: 313 AN: 87312 Hom.: 6 AF XY: 0.00261 AC XY: 129 AN XY: 49498

Gnomad AFR exome AF: 0.0560

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.00813

Gnomad EAS exome AF: 0.0148

Gnomad SAS exome AF: 0.000116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000714

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00204 AC: 2720 AN: 1330546 Hom.: 53 Cov.: 34 AF XY: 0.00176 AC XY: 1155 AN XY: 655764

Gnomad4 AFR exome AF: 0.0561

Gnomad4 AMR exome AF: 0.00509

Gnomad4 ASJ exome AF: 0.00700

Gnomad4 EAS exome AF: 0.0103

Gnomad4 SAS exome AF: 0.000137

Gnomad4 FIN exome AF: 0.0000299

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.00586

GnomAD4 genome AF: 0.0184 AC: 2775 AN: 151032 Hom.: 72 Cov.: 33 AF XY: 0.0175 AC XY: 1292 AN XY: 73836

Gnomad4 AFR AF: 0.0593

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00924

Gnomad4 EAS AF: 0.0163

Gnomad4 SAS AF: 0.000839

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000487

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00175 Hom.: 3

Bravo AF: 0.0206

ESP6500AA AF: 0.0278 AC: 66

ESP6500EA AF: 0.000437 AC: 2

ExAC AF: 0.00388 AC: 70

Asia WGS AF: 0.00785 AC: 27 AN: 3452

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 08, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2022	Variant summary: IDUA c.1225G>C (p.Gly409Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 118354 control chromosomes (gnomAD), predominantly at a frequency of 0.057 within the African or African-American subpopulation in the gnomAD database, including 16 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Nine ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, three as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2015	- -

Mucopolysaccharidosis type 1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The p.Gly409Arg variant has not been previously reported in individuals with mucopolysaccharidosis (MPS) but has been identified in 5.567% (555/9810) of African chromosomes, including 16 homozygotes, and 3 additional homozygotes in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs11934801). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as benign by Invitae, EGL Genetic Diagnostics, and Children's Mercy Hospital and Clinics, likely benign by Illumina, and a VUS by the Children's Hospital of Philadelphia and the NUS Institute of Precision Medicine (Variation ID: 92627). It has also been reported in the heterozygous state and described as a pseudodeficiency allele in an unaffected individual from newborn screening, suggesting that this variant is not pathogenic for disease (PMID: 31133280). In summary, this variant meets criteria to be classified as benign for mucopolysaccharidosis in an autosomal recessive manner based on the high frequency of the variant in the general population. ACMG/AMP Criteria applied: BA1, BS2 (Richards 2015). -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 23, 2020	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2020	Appears to be a hypomorphic allele. Functional studies indicate that this variant reduces protein activity to 61% (Bach et al., 1993), which is not in the pathogenic range for this enzyme.; This variant is associated with the following publications: (PMID: 30709774, 31133280, 28676128, 27335677, 8328452, 21228398) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hurler syndrome Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	18
Dann	Benign	0.93
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.72	T;.
MetaRNN	Benign	0.030	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	2.7e-7	A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.47
Sift	Benign	0.088	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.95	P;.
Vest4		0.24
MVP		0.99
MPC		0.32
ClinPred		0.027	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11934801; hg19: chr4-996555;