NM_000203.5:c.99T>A

Variant names:

• chr4-987183-T-A
• rs10794537
• NM_000203.5:c.99T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000203.5(IDUA):​c.99T>A​(p.His33Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000757 in 1,321,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. The gene IDUA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 38)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.44
• 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]

SLC26A1 Gene-Disease associations (from GenCC):

• nephrolithiasis susceptibility caused by SLC26A1

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

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 (MetaRNN=0.24450672).
• BP6: Variant 4-987183-T-A is Benign according to our data. Variant chr4-987183-T-A is described in ClinVar as Benign. ClinVar VariationId is 2134405.Status of the report is criteria_provided_single_submitter, 1 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.99T>A	p.His33Gln	missense	Exon 1 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_134425.4		c.576+3945A>T		intron	N/A	NP_602297.1	Q9H2B4-2
	IDUA	NR_110313.1		n.187T>A		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.99T>A	p.His33Gln	missense	Exon 1 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.99T>A	p.His33Gln	missense	Exon 1 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398520.6	TSL:1	c.576+3945A>T		intron	N/A	ENSP00000381532.2	Q9H2B4-2

Frequencies

GnomAD3 genomes Cov.: 38

GnomAD4 exome AF: 7.57e-7 AC: 1 AN: 1321296 Hom.: 0 Cov.: 42 AF XY: 0.00000154 AC XY: 1 AN XY: 651284

African (AFR) AF: 0.00 AC: 0 AN: 26630

American (AMR) AF: 0.00 AC: 0 AN: 27900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23200

East Asian (EAS) AF: 0.00 AC: 0 AN: 28562

South Asian (SAS) AF: 0.00 AC: 0 AN: 72678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3894

European-Non Finnish (NFE) AF: 9.52e-7 AC: 1 AN: 1050822

Other (OTH) AF: 0.00 AC: 0 AN: 54706

GnomAD4 genome Cov.: 38

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Mucopolysaccharidosis type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.30
DANN	Benign	0.77
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.041	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-2.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.75	N
REVEL	Uncertain	0.37
Sift	Benign	0.46	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.011
MutPred		0.40		Gain of MoRF binding (P = 0.1031)
MVP		0.55
MPC		0.19
ClinPred		0.044	T
GERP RS		-0.90
PromoterAI		0.084	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.10
gMVP		0.40
Mutation Taster		=95/5	polymorphism

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: rs10794537; hg19: chr4-980971;