rs147498923

Positions:

chr4-987955-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000203.5(IDUA):c.299+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00956 in 1,566,936 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0096 ( 105 hom. )

Consequence

IDUA
NM_000203.5 splice_region, intron

Scores

Splicing: ADA: 0.00003218

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.03

Variant links:

Genes affected

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 links:

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 links:

SLC26A1 (HGNC:):

SLC26A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 4-987955-C-T is Benign according to our data. Variant chr4-987955-C-T is described in ClinVar as [Benign]. Clinvar id is 92640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-987955-C-T is described in Lovd as [Likely_benign]. Variant chr4-987955-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00923 (1405/152258) while in subpopulation NFE AF= 0.0119 (810/67998). AF 95% confidence interval is 0.0112. There are 14 homozygotes in gnomad4. There are 739 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A1	NM_022042.4 linkuse as main transcript	c.*878G>A		3_prime_UTR_variant	3/3	ENST00000398516.3	NP_071325.2	Q9H2B4-1
IDUA	NM_000203.5 linkuse as main transcript	c.299+6C>T		splice_region_variant, intron_variant		ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A1	ENST00000398516 linkuse as main transcript	c.*878G>A		3_prime_UTR_variant	3/3	1	NM_022042.4	ENSP00000381528.2		Q9H2B4-1
IDUA	ENST00000514224.2 linkuse as main transcript	c.299+6C>T		splice_region_variant, intron_variant		2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.00923

AC:

1405

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.00664

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.0304

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0101

AC:

1744

AN:

172956

Hom.:

AF XY:

0.0106

AC XY:

985

AN XY:

93280

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00331

Gnomad ASJ exome

AF:

0.00765

Gnomad EAS exome

AF:

0.0000765

Gnomad SAS exome

AF:

0.00612

Gnomad FIN exome

AF:

0.0304

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.0133

GnomAD4 exome

AF:

0.00960

AC:

13581

AN:

1414678

Hom.:

105

Cov.:

AF XY:

0.00956

AC XY:

6687

AN XY:

699228

show subpopulations

Gnomad4 AFR exome

AF:

0.00192

Gnomad4 AMR exome

AF:

0.00366

Gnomad4 ASJ exome

AF:

0.00788

Gnomad4 EAS exome

AF:

0.0000270

Gnomad4 SAS exome

AF:

0.00541

Gnomad4 FIN exome

AF:

0.0306

Gnomad4 NFE exome

AF:

0.00969

Gnomad4 OTH exome

AF:

0.00950

GnomAD4 genome

AF:

0.00923

AC:

1405

AN:

152258

Hom.:

Cov.:

AF XY:

0.00992

AC XY:

739

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00197

Gnomad4 AMR

AF:

0.00732

Gnomad4 ASJ

AF:

0.00664

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00539

Gnomad4 FIN

AF:

0.0304

Gnomad4 NFE

AF:

0.0119

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.00942

Hom.:

Bravo

AF:

0.00671

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2019	Variant summary: IDUA c.299+6C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.01 in 172956 control chromosomes in the gnomAD database, including 20 homozygotes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (0.0027), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2020	This variant is associated with the following publications: (PMID: 22976768, 19839758, 27884173, 27238910) -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	IDUA: BP4, BS1, BS2; SLC26A1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Mucopolysaccharidosis type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Nephrolithiasis, calcium oxalate

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 16, 2022

- -

Hurler syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0020

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over