4-1002377-G-C

Variant names:

• chr4-1002377-G-C
• rs6831280
• NM_000203.5:c.1081G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000203.5(IDUA):​c.1081G>C​(p.Ala361Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,914 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A361T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14
• Publications: 55 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: ClinGen, Myriad Women’s Health
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000203.5
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1081G>C	p.Ala361Pro	missense	Exon 8 of 14	NP_000194.2
	IDUA	NM_001363576.1		c.685G>C	p.Ala229Pro	missense	Exon 7 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1169G>C		non_coding_transcript_exon	Exon 8 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1081G>C	p.Ala361Pro	missense	Exon 8 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1081G>C	p.Ala361Pro	missense	Exon 8 of 14	ENSP00000247933.4
	IDUA	ENST00000514698.5	TSL:5	n.1188G>C		non_coding_transcript_exon	Exon 5 of 11

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458914 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 725628

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 86028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110898

Other (OTH) AF: 0.0000166 AC: 1 AN: 60290

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 3670

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 20, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.92
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.36
Sift	Benign	0.055	T
Sift4G	Uncertain	0.017	D
Polyphen		0.89	P
Vest4		0.28
MVP		0.90
MPC		0.58
ClinPred		0.50	D
GERP RS		-6.4
Varity_R		0.49
gMVP		0.76
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs6831280; hg19: chr4-996165;