4-987085-A-G

Variant names:

• chr4-987085-A-G
• rs1553914737
• NM_000203.5:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM3 PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1A>G (p.Met1?) variant in IDUA is predicted to cause an N-terminal truncated or absent protein by altering the start codon of the coding sequence. The next in-frame ATG is at position 133. If that ATG is used as a start signal, the lysosomal signal sequence (amino acids 1-27) would be lost (https://www.uniprot.org/uniprotkb/P35475/entry) (PVS1). Two patients with severe MPS1 (Hurler syndrome) are reported to be homozygous for the variant (PMID:27146977, 28752568) (PM3). One patient, from India, had clinical features consistent with a severe presentation of MPS 1 including dysostosis multiplex, coarse facial features, cardiomegaly, and intellectual disability, as well as documented deficient activity of IDUA in leukocytes (PMID:27146977), while a second patient, from Spain, was reported to have a confirmed diagnosis based on IDUA deficiency (PMID:21394825) (PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 8.893e-7 (1/1124490) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Of note, other variants that abolish the start ATG have been identified in individuals with mucopolysaccharidosis type 1 (c.1A>C, ClinVar Variation ID: 550458; c.2T>C, ClinVar Variation ID: 639529). There is a ClinVar entry for c.1A>G (Variation ID:1323098). In summary, this variant, c.1A>G (p.Met1?) meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA355945206/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: -1.98
• 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]

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]

DGKQ (HGNC:2856): (diacylglycerol kinase theta) The protein encoded by this gene contains three cysteine-rich domains, a proline-rich region, and a pleckstrin homology domain with an overlapping Ras-associating domain. It is localized in the speckle domains of the nucleus, and mediates the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.1A>G	p.Met1?	start_lost	Exon 1 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_134425.4		c.576+4043T>C		intron	N/A	NP_602297.1	Q9H2B4-2
	IDUA	NR_110313.1		n.89A>G		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398520.6	TSL:1	c.576+4043T>C		intron	N/A	ENSP00000381532.2	Q9H2B4-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.51e-7 AC: 1 AN: 1332042 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 659440

African (AFR) AF: 0.00 AC: 0 AN: 27084

American (AMR) AF: 0.00 AC: 0 AN: 30198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22438

East Asian (EAS) AF: 0.00 AC: 0 AN: 29388

South Asian (SAS) AF: 0.00 AC: 0 AN: 74140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3820

European-Non Finnish (NFE) AF: 9.47e-7 AC: 1 AN: 1056520

Other (OTH) AF: 0.00 AC: 0 AN: 54412

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Mucopolysaccharidosis type 1 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	11
DANN	Benign	0.68
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.084	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.33	T
PhyloP100		-2.0
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.029	D
Polyphen		0.0	B
Vest4		0.76
MutPred		0.99		Loss of glycosylation at P6 (P = 0.0238)
MVP		0.86
ClinPred		0.64	D
GERP RS		-2.0
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.72
Mutation Taster		=6/194	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553914737; hg19: chr4-980873; COSMIC: COSV56106545; COSMIC: COSV56106545;