chr4-987946-C-T

Variant names:

• chr4-987946-C-T
• rs147490060
• NM_000203.5:c.296C>T

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.296C>T variant in IDUA is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 33 (p.Thr99Ile). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.01845 in the African/African American population. This 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: 280992). 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 January 2, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2801158/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.0055 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (8 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: 1.06
• Publications: 6 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.296C>T	p.Thr99Ile	missense	Exon 2 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_022042.4	MANE Select	c.*887G>A		3_prime_UTR	Exon 3 of 3	NP_071325.2
	SLC26A1	NM_213613.4		c.*887G>A		3_prime_UTR	Exon 4 of 4	NP_998778.1	Q9H2B4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.296C>T	p.Thr99Ile	missense	Exon 2 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.296C>T	p.Thr99Ile	missense	Exon 2 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398516.3	TSL:1 MANE Select	c.*887G>A		3_prime_UTR	Exon 3 of 3	ENSP00000381528.2	Q9H2B4-1

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 834 AN: 152238 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00155 AC: 290 AN: 187384 AF XY: 0.00109

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000519

Gnomad OTH exome AF: 0.000201

GnomAD4 exome AF: 0.000524 AC: 746 AN: 1424938 Hom.: 8 Cov.: 30 AF XY: 0.000472 AC XY: 333 AN XY: 705302

African (AFR) AF: 0.0192 AC: 626 AN: 32534

American (AMR) AF: 0.00106 AC: 42 AN: 39648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25496

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37600

South Asian (SAS) AF: 0.0000243 AC: 2 AN: 82158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49458

Middle Eastern (MID) AF: 0.000547 AC: 3 AN: 5482

European-Non Finnish (NFE) AF: 0.0000128 AC: 14 AN: 1093634

Other (OTH) AF: 0.000984 AC: 58 AN: 58928

GnomAD4 genome AF: 0.00548 AC: 835 AN: 152356 Hom.: 7 Cov.: 33 AF XY: 0.00523 AC XY: 390 AN XY: 74508

African (AFR) AF: 0.0193 AC: 803 AN: 41594

American (AMR) AF: 0.00163 AC: 25 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00168 Hom.: 2

Bravo AF: 0.00625

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0159 AC: 69

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00157 AC: 187

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Mucopolysaccharidosis type 1 (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0069	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.29
Sift	Benign	0.55	T
Sift4G	Benign	0.52	T
Polyphen		0.0040	B
Vest4		0.37
MVP		0.97
MPC		0.27
ClinPred		0.0015	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.39
Mutation Taster		=87/13	polymorphism

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: rs147490060; hg19: chr4-981734;