4-1002767-G-C

Variant names:

• chr4-1002767-G-C
• rs11934801
• NM_000203.5:c.1225G>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.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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G409E) has been classified as Uncertain significance. The gene IDUA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.018 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (53 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:11
• Conservation: PhyloP100: 0.768
• Publications: 16 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

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 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 Benign/Likely_benign. ClinVar VariationId is 92627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1225G>C	p.Gly409Arg	missense	Exon 9 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.829G>C	p.Gly277Arg	missense	Exon 8 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1313G>C		non_coding_transcript_exon	Exon 9 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1225G>C	p.Gly409Arg	missense	Exon 9 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1225G>C	p.Gly409Arg	missense	Exon 9 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1300G>C	p.Gly434Arg	missense	Exon 10 of 15	ENSP00000632448.1

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

GnomAD2 exomes AF: 0.00358 AC: 313 AN: 87312 AF XY: 0.00261

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 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

African (AFR) AF: 0.0561 AC: 1507 AN: 26860

American (AMR) AF: 0.00509 AC: 150 AN: 29492

Ashkenazi Jewish (ASJ) AF: 0.00700 AC: 165 AN: 23574

East Asian (EAS) AF: 0.0103 AC: 305 AN: 29682

South Asian (SAS) AF: 0.000137 AC: 10 AN: 73162

European-Finnish (FIN) AF: 0.0000299 AC: 1 AN: 33404

Middle Eastern (MID) AF: 0.00382 AC: 15 AN: 3930

European-Non Finnish (NFE) AF: 0.000230 AC: 243 AN: 1055108

Other (OTH) AF: 0.00586 AC: 324 AN: 55334

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

African (AFR) AF: 0.0593 AC: 2434 AN: 41054

American (AMR) AF: 0.0106 AC: 161 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00924 AC: 32 AN: 3462

East Asian (EAS) AF: 0.0163 AC: 83 AN: 5082

South Asian (SAS) AF: 0.000839 AC: 4 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10406

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000487 AC: 33 AN: 67718

Other (OTH) AF: 0.0128 AC: 27 AN: 2108

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Mucopolysaccharidosis type 1 (4)
-	1	3	not specified (4)
-	-	3	not provided (3)
-	1	1	Hurler syndrome (2)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.77
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.47
Sift	Benign	0.088	T
Sift4G	Benign	0.12	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
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs11934801; hg19: chr4-996555;