rs200237798

Positions:

• chr4-1000677-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000203.5(IDUA):​c.365G>A​(p.Arg122Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,612,080 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R122R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.74

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21126631).
• BP6: Variant 4-1000677-G-A is Benign according to our data. Variant chr4-1000677-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 350221.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr4-1000677-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.365G>A	p.Arg122Lys	missense_variant	3/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.365G>A	p.Arg122Lys	missense_variant	3/14	2	NM_000203.5	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152220 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000124 AC: 31 AN: 250034 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135676

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000287 AC: 419 AN: 1459860 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 214 AN XY: 726222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000360

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152220 Hom.: 0 Cov.: 34 AF XY: 0.000134 AC XY: 10 AN XY: 74364

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000907 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis type 1 Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D;.;D;D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.43	T;T;.;.
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.9	L;.;.;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.73	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.40	T;T;T;T
Sift4G	Benign	0.79	T;T;T;T
Polyphen		0.51	P;.;.;.
Vest4		0.087
MVP		0.98
MPC		0.20
ClinPred		0.041	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs200237798; hg19: chr4-994465;