rs58037052

chr4-987885-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000203.5(IDUA):c.235G>A(p.Ala79Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00158 in 1,611,212 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0085 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (15 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts U:1 B:8 O:3
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-987886-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1458769.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0113580525).
• BP6: Variant 4-987885-G-A is Benign according to our data. Variant chr4-987885-G-A is described in ClinVar as [Likely_benign, other]. Clinvar id is 195038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-987885-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00846 (1289/152316) while in subpopulation AFR AF= 0.0299 (1242/41562). AF 95% confidence interval is 0.0285. There are 15 homozygotes in gnomad4. There are 620 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.235G>A	p.Ala79Thr	missense_variant	2/14	ENST00000514224.2
SLC26A1	NM_022042.4	c.*948C>T		3_prime_UTR_variant	3/3	ENST00000398516.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.235G>A	p.Ala79Thr	missense_variant	2/14	2	NM_000203.5	P1
SLC26A1	ENST00000398516.3	c.*948C>T		3_prime_UTR_variant	3/3	1	NM_022042.4	P1

Frequencies

GnomAD3 genomes AF: 0.00848 AC: 1291 AN: 152198 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

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: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00239 AC: 572 AN: 239166 Hom.: 7 AF XY: 0.00173 AC XY: 225 AN XY: 130330

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000856

Gnomad OTH exome AF: 0.000850

GnomAD4 exome AF: 0.000866 AC: 1263 AN: 1458896 Hom.: 15 Cov.: 30 AF XY: 0.000733 AC XY: 532 AN XY: 725620

Gnomad4 AFR exome AF: 0.0314

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000931

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00846 AC: 1289 AN: 152316 Hom.: 15 Cov.: 33 AF XY: 0.00832 AC XY: 620 AN XY: 74490

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00251 Hom.: 4

Bravo AF: 0.00964

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0285 AC: 125

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00285 AC: 344

Asia WGS AF: 0.00144 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Uncertain:1 Benign:8 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3 Other:1

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 27, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 27, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2018	This variant is associated with the following publications: (PMID: 27939258) -

Mucopolysaccharidosis type 1 Benign:1 Other:2

not provided, no classification provided	literature only	GeneReviews	-	Pseudodeficiency variants -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
other, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2018	- pseudodeficiency allele

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 01, 2021	Variant summary: IDUA c.235G>A (p.Ala79Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 270526 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 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 a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.235G>A, also has been reported in the literature as a well-known pseudodeficiency allele, prevalent in the African American subpopulation. Individuals with pseudodeficiency allele(s) exhibit decreased alpha-L-iduronidase enzyme activity in biochemical assays using artificial substrates, but otherwise show no evidence of disease (see e.g. in Clarke_2016). Seven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign pseudodeficiency allele (n=6) or VUS (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hurler syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

May 16, 2018

- -

Calcium oxalate urolithiasis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.087
Eigen_PC	Benign	0.026
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;N;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.75
MVP		0.98
MPC		0.74
ClinPred		0.023	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs58037052; hg19: chr4-981673;