rs1001972534

chr4-987148-C-Gchr4-987148-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000203.5(IDUA):c.64C>G(p.Pro22Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000494 in 1,415,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P22L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 36)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.691

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]

SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2420077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.64C>G	p.Pro22Ala	missense_variant	1/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.64C>G	p.Pro22Ala	missense_variant	1/14	2	NM_000203.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152044 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000237 AC: 3 AN: 1263616 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 620816

Gnomad4 AFR exome AF: 0.0000801

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000192

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152044 Hom.: 0 Cov.: 36 AF XY: 0.0000404 AC XY: 3 AN XY: 74272

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.0000982

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 25, 2022	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 22 of the IDUA protein (p.Pro22Ala). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with IDUA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1000369). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IDUA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2021

The p.P22A variant (also known as c.64C>G), located in coding exon 1 of the IDUA gene, results from a C to G substitution at nucleotide position 64. The proline at codon 22 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	1.3
Dann	Benign	0.39
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.44	T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.10	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.54	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0010	B;.
Vest4		0.21
MutPred		0.29		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		0.85
MPC		0.18
ClinPred		0.022	T
GERP RS		-0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.44

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: rs1001972534; hg19: chr4-980936;