4-1002980-T-G

Variant names:

• chr4-1002980-T-G
• rs115134980
• NM_000203.5:c.1402+36T>G

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.1402+36T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,240,934 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: 0.000012 (0 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.42
• Publications: 10 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=-0.92).

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.1402+36T>G		intron	N/A	NP_000194.2
	IDUA	NM_001363576.1		c.1006+36T>G		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1490+36T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1402+36T>G		intron	N/A	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1402+36T>G		intron	N/A	ENSP00000247933.4
	IDUA	ENST00000502829.1	TSL:2	n.204+36T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000121 AC: 15 AN: 1240934 Hom.: 0 Cov.: 36 AF XY: 0.00000991 AC XY: 6 AN XY: 605242

African (AFR) AF: 0.00 AC: 0 AN: 24716

American (AMR) AF: 0.00 AC: 0 AN: 14848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18968

East Asian (EAS) AF: 0.00 AC: 0 AN: 27664

South Asian (SAS) AF: 0.00 AC: 0 AN: 58258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4794

European-Non Finnish (NFE) AF: 0.0000139 AC: 14 AN: 1010188

Other (OTH) AF: 0.0000196 AC: 1 AN: 51040

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 219

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.15
PhyloP100		-3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs115134980; hg19: chr4-996768;