4-987087-G-A

Position:

• chr4-987087-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000203.5(IDUA):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IDUA NM_000203.5 start_lost
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.193

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000203.5 (IDUA) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-987087-G-A is Pathogenic according to our data. Variant chr4-987087-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.3G>A	p.Met1?	start_lost	1/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.3G>A	p.Met1?	start_lost	1/14	2	NM_000203.5	ENSP00000425081	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000151 AC: 2 AN: 1327324 Hom.: 0 Cov.: 30 AF XY: 0.00000305 AC XY: 2 AN XY: 656658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 28, 2023

Variant summary: IDUA c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon (M133). Two of three in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 106268 control chromosomes. c.3G>A has been reported in the literature in compound heterozygosity with a nonsense variant (Tyr343*) in one individual affected with Mucopolysaccharidosis Type 1 (Lee-Chen_1997). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants upstream of the nearest downstream initiation codon (M133) have been classified as pathogenic by our laboratory. The following publication has been ascertained in the context of this evaluation (PMID: 9391892). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hurler syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	-0.72	N;N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		0.0050	B;.
Vest4		0.67
MutPred		0.99		Loss of glycosylation at P6 (P = 0.0238);Loss of glycosylation at P6 (P = 0.0238);
MVP		0.92
ClinPred		0.81	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553914740; hg19: chr4-980875;