rs794727896

Variant names:

• chr4-1002459-C-A
• rs794727896
• NM_000203.5:c.1163C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1002459-C-A
• chr4-1002459-C-G
• chr4-1002459-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000203.5(IDUA):​c.1163C>A​(p.Thr388Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,401,078 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T388M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 5.91
• Publications: 7 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

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000203.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-1002459-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 558615.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 4-1002459-C-A is Pathogenic according to our data. Variant chr4-1002459-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 198696.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.1163C>A	p.Thr388Lys	missense	Exon 8 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.767C>A	p.Thr256Lys	missense	Exon 7 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1251C>A		non_coding_transcript_exon	Exon 8 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1163C>A	p.Thr388Lys	missense	Exon 8 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1163C>A	p.Thr388Lys	missense	Exon 8 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1238C>A	p.Thr413Lys	missense	Exon 9 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000651 AC: 1 AN: 153708 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000911

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1401078 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 691618

African (AFR) AF: 0.00 AC: 0 AN: 31566

American (AMR) AF: 0.00 AC: 0 AN: 36040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25116

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35828

South Asian (SAS) AF: 0.00 AC: 0 AN: 79736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081336

Other (OTH) AF: 0.00 AC: 0 AN: 58072

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Mucopolysaccharidosis type 1 (4)
2	-	-	not provided (2)
-	1	-	Hurler syndrome (1)
1	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.99
MPC		0.83
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.80
Mutation Taster		=2/98	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: rs794727896; hg19: chr4-996247;