rs199722340

Variant names:

• chr4-1003402-C-G
• rs199722340
• NM_000203.5:c.1582C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-1003402-C-G
• chr4-1003402-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000203.5(IDUA):​c.1582C>G​(p.Pro528Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,525,012 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P528L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0080 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (23 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.265
• 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: 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

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000203.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.002762109).
• BP6: Variant 4-1003402-C-G is Benign according to our data. Variant chr4-1003402-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 526839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.008 (1217/152184) while in subpopulation AFR AF = 0.0273 (1133/41544). AF 95% confidence interval is 0.026. There are 16 homozygotes in GnomAd4. There are 558 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

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.1582C>G	p.Pro528Ala	missense	Exon 11 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1186C>G	p.Pro396Ala	missense	Exon 10 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1670C>G		non_coding_transcript_exon	Exon 11 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1582C>G	p.Pro528Ala	missense	Exon 11 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1582C>G	p.Pro528Ala	missense	Exon 11 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1657C>G	p.Pro553Ala	missense	Exon 12 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 1214 AN: 152076 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00130 AC: 158 AN: 121722 AF XY: 0.00120

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000885

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.000823 AC: 1130 AN: 1372828 Hom.: 23 Cov.: 33 AF XY: 0.000755 AC XY: 511 AN XY: 677226

African (AFR) AF: 0.0283 AC: 854 AN: 30182

American (AMR) AF: 0.00194 AC: 68 AN: 35042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24732

East Asian (EAS) AF: 0.00 AC: 0 AN: 34740

South Asian (SAS) AF: 0.000102 AC: 8 AN: 78236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33418

Middle Eastern (MID) AF: 0.00331 AC: 14 AN: 4234

European-Non Finnish (NFE) AF: 0.0000521 AC: 56 AN: 1074988

Other (OTH) AF: 0.00227 AC: 130 AN: 57256

GnomAD4 genome AF: 0.00800 AC: 1217 AN: 152184 Hom.: 16 Cov.: 33 AF XY: 0.00750 AC XY: 558 AN XY: 74414

African (AFR) AF: 0.0273 AC: 1133 AN: 41544

American (AMR) AF: 0.00438 AC: 67 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67980

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00394 Hom.: 0

Bravo AF: 0.00995

ExAC AF: 0.000902 AC: 62

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	1.3
DANN	Benign	0.47
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.91	L
PhyloP100		0.27
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.15
Sift	Benign	0.77	T
Sift4G	Benign	0.77	T
Polyphen		0.0010	B
Vest4		0.086
MVP		0.76
MPC		0.42
ClinPred		0.00045	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.56
Mutation Taster		=96/4	polymorphism

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: rs199722340; hg19: chr4-997190;