4-987085-A-G

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.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,332,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.98

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 [Likely_pathogenic] in ClinVar as 557150
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-987085-A-G is Pathogenic according to our data. Variant chr4-987085-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1323098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-987085-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

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

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

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: 9.47e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2023

This sequence change affects the initiator methionine of the IDUA mRNA. The next in-frame methionine is located at codon 133. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 27146977, 31236806). ClinVar contains an entry for this variant (Variation ID: 1323098). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	-0.70	N;N
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.0	B;.
Vest4		0.76
MutPred		0.99		Loss of glycosylation at P6 (P = 0.0238);Loss of glycosylation at P6 (P = 0.0238);
MVP		0.86
ClinPred		0.64	D
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.72

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-980873; COSMIC: COSV56106545; COSMIC: COSV56106545;