rs6831021

Variant names:

• chr4-1002224-G-C
• rs6831021
• NM_000203.5:c.973-45G>C

Your query was ambiguous. Multiple possible variants found:

• chr4-1002224-G-C
• chr4-1002224-G-A

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.973-45G>C 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 1,579,492 control chromosomes in the GnomAD database, including 22,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene IDUA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.17 (2418 hom., cov: 34)
  • Exomes 𝑓: 0.16 (20215 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.97
• Publications: 11 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

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

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

• BP4: Computational evidence support a benign effect (REVEL=0.178).
• BP6: Variant 4-1002224-G-C is Benign according to our data. Variant chr4-1002224-G-C is described in ClinVar as Benign. ClinVar VariationId is 255530.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.973-45G>C		intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.577-45G>C		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1061-45G>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.973-45G>C		intron	N/A	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.973-45G>C		intron	N/A	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1048-45G>C		intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26508 AN: 151900 Hom.: 2422 Cov.: 34

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.177 AC: 33662 AN: 190542 AF XY: 0.186

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.0818

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.162 AC: 230918 AN: 1427474 Hom.: 20215 Cov.: 35 AF XY: 0.166 AC XY: 117298 AN XY: 707398

African (AFR) AF: 0.229 AC: 7452 AN: 32544

American (AMR) AF: 0.0873 AC: 3424 AN: 39242

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4117 AN: 25558

East Asian (EAS) AF: 0.170 AC: 6357 AN: 37374

South Asian (SAS) AF: 0.299 AC: 24714 AN: 82758

European-Finnish (FIN) AF: 0.152 AC: 7513 AN: 49400

Middle Eastern (MID) AF: 0.203 AC: 1164 AN: 5734

European-Non Finnish (NFE) AF: 0.152 AC: 166177 AN: 1095822

Other (OTH) AF: 0.169 AC: 10000 AN: 59042

GnomAD4 genome AF: 0.174 AC: 26507 AN: 152018 Hom.: 2418 Cov.: 34 AF XY: 0.174 AC XY: 12954 AN XY: 74336

African (AFR) AF: 0.220 AC: 9106 AN: 41454

American (AMR) AF: 0.124 AC: 1898 AN: 15296

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

East Asian (EAS) AF: 0.199 AC: 1019 AN: 5130

South Asian (SAS) AF: 0.300 AC: 1447 AN: 4820

European-Finnish (FIN) AF: 0.144 AC: 1522 AN: 10586

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10333 AN: 67948

Other (OTH) AF: 0.183 AC: 387 AN: 2112

Alfa AF: 0.100 Hom.: 205

Bravo AF: 0.172

Asia WGS AF: 0.248 AC: 865 AN: 3476

ClinVar

ClinVar submissions

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	-0.85
CADD	Benign	1.5
DANN	Uncertain	0.98
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs6831021; hg19: chr4-996012; COSMIC: COSV56101287; COSMIC: COSV56101287;