4-987183-T-G

Variant names:

• chr4-987183-T-G
• rs10794537
• NM_000203.5:c.99T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.99T>G variant in IDUA is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 33 (p.His33Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.9605 (65474/68164 alleles; 31451 homozygotes; Grpmax Filtering AF 95% confidence = 0.9544) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92651). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA145894/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.85 (55748 hom., cov: 38)
  • Exomes 𝑓: 0.81 (435164 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign reviewed by expert panel B:16
• Conservation: PhyloP100: -2.44
• Publications: 40 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]

SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]

SLC26A1 Gene-Disease associations (from GenCC):

• nephrolithiasis susceptibility caused by SLC26A1

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.99T>G	p.His33Gln	missense	Exon 1 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_134425.4		c.576+3945A>C		intron	N/A	NP_602297.1	Q9H2B4-2
	IDUA	NR_110313.1		n.187T>G		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.99T>G	p.His33Gln	missense	Exon 1 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.99T>G	p.His33Gln	missense	Exon 1 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398520.6	TSL:1	c.576+3945A>C		intron	N/A	ENSP00000381532.2	Q9H2B4-2

Frequencies

GnomAD3 genomes AF: 0.853 AC: 129624 AN: 152032 Hom.: 55703 Cov.: 38

Gnomad AFR AF: 0.958

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.891

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.789

Gnomad MID AF: 0.939

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.860

GnomAD2 exomes AF: 0.839 AC: 67457 AN: 80392 AF XY: 0.849

Gnomad AFR exome AF: 0.962

Gnomad AMR exome AF: 0.797

Gnomad ASJ exome AF: 0.895

Gnomad EAS exome AF: 0.855

Gnomad FIN exome AF: 0.787

Gnomad NFE exome AF: 0.803

Gnomad OTH exome AF: 0.834

GnomAD4 exome AF: 0.810 AC: 1070032 AN: 1320386 Hom.: 435164 Cov.: 42 AF XY: 0.815 AC XY: 530301 AN XY: 650812

African (AFR) AF: 0.965 AC: 25675 AN: 26620

American (AMR) AF: 0.801 AC: 22320 AN: 27848

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 20741 AN: 23180

East Asian (EAS) AF: 0.857 AC: 24488 AN: 28560

South Asian (SAS) AF: 0.928 AC: 67400 AN: 72602

European-Finnish (FIN) AF: 0.790 AC: 25954 AN: 32854

Middle Eastern (MID) AF: 0.919 AC: 3579 AN: 3894

European-Non Finnish (NFE) AF: 0.794 AC: 834224 AN: 1050164

Other (OTH) AF: 0.835 AC: 45651 AN: 54664

GnomAD4 genome AF: 0.853 AC: 129714 AN: 152140 Hom.: 55748 Cov.: 38 AF XY: 0.854 AC XY: 63531 AN XY: 74384

African (AFR) AF: 0.958 AC: 39799 AN: 41544

American (AMR) AF: 0.819 AC: 12514 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.891 AC: 3092 AN: 3470

East Asian (EAS) AF: 0.853 AC: 4405 AN: 5166

South Asian (SAS) AF: 0.935 AC: 4516 AN: 4832

European-Finnish (FIN) AF: 0.789 AC: 8337 AN: 10568

Middle Eastern (MID) AF: 0.935 AC: 273 AN: 292

European-Non Finnish (NFE) AF: 0.800 AC: 54332 AN: 67954

Other (OTH) AF: 0.861 AC: 1821 AN: 2116

Alfa AF: 0.816 Hom.: 6355

Bravo AF: 0.858

TwinsUK AF: 0.786 AC: 2916

ALSPAC AF: 0.797 AC: 3073

ExAC AF: 0.853 AC: 10917

Asia WGS AF: 0.916 AC: 3163 AN: 3452

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Mucopolysaccharidosis type 1 (4)
-	-	3	not provided (3)
-	-	1	Hurler syndrome (1)
-	-	1	Mucopolysaccharidosis, MPS-I-H/S (1)
-	-	1	Mucopolysaccharidosis, MPS-I-S (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.34
DANN	Benign	0.67
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.041	T
MetaRNN	Benign	7.3e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-2.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.75	N
REVEL	Uncertain	0.39
Sift	Benign	0.46	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.011
MutPred		0.40		Gain of MoRF binding (P = 0.1031)
MPC		0.19
ClinPred		0.0017	T
GERP RS		-0.90
PromoterAI		0.014	Neutral
Varity_R		0.10
gMVP		0.40
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10794537; hg19: chr4-980971; COSMIC: COSV56101815; COSMIC: COSV56101815;