rs368368416

Variant names:

• chr4-1003022-G-A
• rs368368416
• NM_000203.5:c.1403-14G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1003022-G-A
• chr4-1003022-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000203.5(IDUA):​c.1403-14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000756 in 1,322,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.421
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1403-14G>A		intron_variant	Intron 9 of 13	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.1007-14G>A		intron_variant	Intron 8 of 12		NP_001350505.1
IDUA	NR_110313.1	n.1491-14G>A		intron_variant	Intron 9 of 13
IDUA	XM_047415650.1	c.1403-14G>A		intron_variant	Intron 9 of 11		XP_047271606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1403-14G>A		intron_variant	Intron 9 of 13	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.56e-7 AC: 1 AN: 1322254 Hom.: 0 Cov.: 37 AF XY: 0.00000153 AC XY: 1 AN XY: 652250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27224

American (AMR) AF: 0.00 AC: 0 AN: 27072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22876

East Asian (EAS) AF: 0.00 AC: 0 AN: 29758

South Asian (SAS) AF: 0.00 AC: 0 AN: 70898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5408

European-Non Finnish (NFE) AF: 9.52e-7 AC: 1 AN: 1050886

Other (OTH) AF: 0.00 AC: 0 AN: 54626

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.67
PhyloP100		-0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs368368416; hg19: chr4-996810;