4-1003022-G-T

Variant names:

• chr4-1003022-G-T
• rs368368416
• NM_000203.5:c.1403-14G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000203.5(IDUA):​c.1403-14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,474,276 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (171 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.421
• 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]

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 -16 ACMG points.

• BP6: Variant 4-1003022-G-T is Benign according to our data. Variant chr4-1003022-G-T is described in ClinVar as Benign. ClinVar VariationId is 255523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.052 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.1403-14G>T		intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1007-14G>T		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1491-14G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1403-14G>T		intron	N/A	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1403-14G>T		intron	N/A	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1478-14G>T		intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 329 AN: 151962 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00660

Gnomad SAS AF: 0.0588

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00905 AC: 954 AN: 105372 AF XY: 0.0124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000600

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00334 AC: 4422 AN: 1322204 Hom.: 171 Cov.: 37 AF XY: 0.00476 AC XY: 3103 AN XY: 652222

African (AFR) AF: 0.000110 AC: 3 AN: 27224

American (AMR) AF: 0.000148 AC: 4 AN: 27072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22876

East Asian (EAS) AF: 0.0162 AC: 481 AN: 29756

South Asian (SAS) AF: 0.0518 AC: 3668 AN: 70850

European-Finnish (FIN) AF: 0.0000298 AC: 1 AN: 33506

Middle Eastern (MID) AF: 0.00314 AC: 17 AN: 5408

European-Non Finnish (NFE) AF: 0.0000314 AC: 33 AN: 1050886

Other (OTH) AF: 0.00394 AC: 215 AN: 54626

GnomAD4 genome AF: 0.00216 AC: 329 AN: 152072 Hom.: 8 Cov.: 33 AF XY: 0.00331 AC XY: 246 AN XY: 74362

African (AFR) AF: 0.000193 AC: 8 AN: 41528

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00662 AC: 34 AN: 5134

South Asian (SAS) AF: 0.0576 AC: 278 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67934

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000457

Asia WGS AF: 0.0440 AC: 149 AN: 3436

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Mucopolysaccharidosis type 1 (3)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.53
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368368416; hg19: chr4-996810; COSMIC: COSV56105495; COSMIC: COSV56105495;