rs6811373

Variant names:

• chr4-1002209-A-G
• rs6811373
• NM_000203.5:c.972+48A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000203.5(IDUA):​c.972+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,570,730 control chromosomes in the GnomAD database, including 22,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2424 hom., cov: 34)
  • Exomes 𝑓: 0.16 (20025 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.175
• Publications: 10 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: ClinGen, Myriad Women’s Health
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.157).
• BP6: Variant 4-1002209-A-G is Benign according to our data. Variant chr4-1002209-A-G is described in ClinVar as Benign. ClinVar VariationId is 255529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.287 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.972+48A>G		intron	N/A	NP_000194.2
	IDUA	NM_001363576.1		c.576+48A>G		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1060+48A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.972+48A>G		intron	N/A	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.972+48A>G		intron	N/A	ENSP00000247933.4
	IDUA	ENST00000514698.5	TSL:5	n.1020A>G		non_coding_transcript_exon	Exon 5 of 11

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26534 AN: 151786 Hom.: 2428 Cov.: 34

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.175 AC: 31234 AN: 178824 AF XY: 0.184

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0817

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.162 AC: 229238 AN: 1418828 Hom.: 20025 Cov.: 35 AF XY: 0.165 AC XY: 116173 AN XY: 702020

African (AFR) AF: 0.229 AC: 7399 AN: 32280

American (AMR) AF: 0.0876 AC: 3315 AN: 37844

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4088 AN: 25392

East Asian (EAS) AF: 0.169 AC: 6240 AN: 36918

South Asian (SAS) AF: 0.298 AC: 24352 AN: 81788

European-Finnish (FIN) AF: 0.152 AC: 7451 AN: 49134

Middle Eastern (MID) AF: 0.202 AC: 1156 AN: 5718

European-Non Finnish (NFE) AF: 0.151 AC: 165278 AN: 1091000

Other (OTH) AF: 0.170 AC: 9959 AN: 58754

GnomAD4 genome AF: 0.175 AC: 26533 AN: 151902 Hom.: 2424 Cov.: 34 AF XY: 0.175 AC XY: 12968 AN XY: 74286

African (AFR) AF: 0.220 AC: 9118 AN: 41406

American (AMR) AF: 0.124 AC: 1902 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3468

East Asian (EAS) AF: 0.200 AC: 1025 AN: 5130

South Asian (SAS) AF: 0.300 AC: 1445 AN: 4816

European-Finnish (FIN) AF: 0.144 AC: 1522 AN: 10572

Middle Eastern (MID) AF: 0.231 AC: 67 AN: 290

European-Non Finnish (NFE) AF: 0.152 AC: 10339 AN: 67908

Other (OTH) AF: 0.183 AC: 387 AN: 2110

Alfa AF: 0.157 Hom.: 376

Bravo AF: 0.172

Asia WGS AF: 0.248 AC: 867 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.5
DANN	Benign	0.11
PhyloP100		0.17
Mutation Taster		=99/1	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: rs6811373; hg19: chr4-995997; COSMIC: COSV56101281; COSMIC: COSV56101281;