chr4-1003307-T-C

Variant names:

• chr4-1003307-T-C
• rs1131853
• NM_000203.5:c.1525-38T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000203.5(IDUA):​c.1525-38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,403,314 control chromosomes in the GnomAD database, including 35,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3793 hom., cov: 32)
  • Exomes 𝑓: 0.22 (31264 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.138
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-1003307-T-C is Benign according to our data. Variant chr4-1003307-T-C is described in ClinVar as Benign. ClinVar VariationId is 255525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

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.1525-38T>C		intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1129-38T>C		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1613-38T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1525-38T>C		intron	N/A	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1525-38T>C		intron	N/A	ENSP00000247933.4	P35475-1
	IDUA	ENST00000871737.1		c.1526T>C	p.Leu509Pro	missense splice_region	Exon 11 of 14	ENSP00000541796.1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33600 AN: 151414 Hom.: 3799 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.192 AC: 6640 AN: 34608 AF XY: 0.207

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.0978

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.168

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.220 AC: 274963 AN: 1251794 Hom.: 31264 Cov.: 33 AF XY: 0.222 AC XY: 136575 AN XY: 614844

African (AFR) AF: 0.237 AC: 5785 AN: 24364

American (AMR) AF: 0.146 AC: 2090 AN: 14318

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 5226 AN: 18942

East Asian (EAS) AF: 0.182 AC: 5004 AN: 27492

South Asian (SAS) AF: 0.319 AC: 19270 AN: 60344

European-Finnish (FIN) AF: 0.188 AC: 5880 AN: 31338

Middle Eastern (MID) AF: 0.345 AC: 1219 AN: 3536

European-Non Finnish (NFE) AF: 0.214 AC: 218682 AN: 1020020

Other (OTH) AF: 0.230 AC: 11807 AN: 51440

GnomAD4 genome AF: 0.222 AC: 33595 AN: 151520 Hom.: 3793 Cov.: 32 AF XY: 0.221 AC XY: 16333 AN XY: 74036

African (AFR) AF: 0.231 AC: 9550 AN: 41342

American (AMR) AF: 0.191 AC: 2907 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 1001 AN: 3470

East Asian (EAS) AF: 0.220 AC: 1115 AN: 5068

South Asian (SAS) AF: 0.333 AC: 1602 AN: 4810

European-Finnish (FIN) AF: 0.178 AC: 1866 AN: 10488

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.217 AC: 14708 AN: 67782

Other (OTH) AF: 0.255 AC: 535 AN: 2100

Alfa AF: 0.207 Hom.: 421

Bravo AF: 0.220

Asia WGS AF: 0.295 AC: 1011 AN: 3414

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Mucopolysaccharidosis type 1 (1)
-	-	1	Mucopolysaccharidosis, MPS-I-H/S (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.0
DANN	Benign	0.21
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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: rs1131853; hg19: chr4-997095; COSMIC: COSV56104855; COSMIC: COSV56104855;