4-1004391-T-G

Variant names:

• chr4-1004391-T-G
• rs387906504
• NM_000203.5:c.1960T>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PM4 PP5_Very_Strong

The NM_000203.5(IDUA):​c.1960T>G​(p.Ter654Glyext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV001577978: This variant has been reported to affect IDUA protein function (PMID:7550232)." and additional evidence is available in ClinVar. The gene IDUA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 stop_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 0.123
• Publications: 8 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: Myriad Women’s Health, ClinGen
• Scheie syndrome

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

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

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

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001577978: This variant has been reported to affect IDUA protein function (PMID: 7550232).; SCV005619864: When the variant was expressed in COS cells, the intracellular activity of IDUA was low (negative control 1.3 (U/mg cell protein, wild type 14.5 (U/mg cell protein, variant 2.5 (U/mg cell protein), approximately 10% wild type ( PMID: 7550232).
• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000203.5 Downstream stopcodon found after 666 codons.
• PP5: Variant 4-1004391-T-G is Pathogenic according to our data. Variant chr4-1004391-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 11920.Status of the report is reviewed_by_expert_panel, 3 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1960T>G	p.Ter654Glyext*?	stop_lost	Exon 14 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1564T>G	p.Ter522Glyext*?	stop_lost	Exon 13 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.2052T>G		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1960T>G	p.Ter654Glyext*?	stop_lost	Exon 14 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1960T>G	p.Ter654Glyext*?	stop_lost	Exon 14 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.2035T>G	p.Ter679Glyext*?	stop_lost	Exon 15 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457954 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725374

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4844

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Mucopolysaccharidosis type 1 (3)
1	-	-	Mucopolysaccharidosis, MPS-I-H/S (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.30
DANN	Benign	0.50
Eigen	Benign	0.055
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.064	N
PhyloP100		0.12
Vest4		0.15
GERP RS		-0.75
Mutation Taster		=6/194	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906504; hg19: chr4-998179;