rs76722191

chr4-1002154-T-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 3P and 14B. PM1 PP3 BP4_Moderate BP6_Very_Strong BS1

The NM_000203.5(IDUA):c.965T>A(p.Val322Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000506 in 1,556,798 control chromosomes in the GnomAD database, including 2 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. V322L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts B:3 O:2
• Conservation: PhyloP100: 4.78

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000203.5
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, M_CAP, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.073826075).
• BP6: Variant 4-1002154-T-A is Benign according to our data. Variant chr4-1002154-T-A is described in ClinVar as [Likely_benign, other]. Clinvar id is 222992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1002154-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00249 (379/152160) while in subpopulation AFR AF= 0.00845 (351/41518). AF 95% confidence interval is 0.00772. There are 0 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.965T>A	p.Val322Glu	missense_variant	7/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.965T>A	p.Val322Glu	missense_variant	7/14	2	NM_000203.5	P1
IDUA	ENST00000247933.9	c.965T>A	p.Val322Glu	missense_variant	7/14	1		P1
IDUA	ENST00000514698.5	n.965T>A		non_coding_transcript_exon_variant	5/11	5
IDUA	ENST00000652070.1	n.1021T>A		non_coding_transcript_exon_variant	6/13

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152042 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00843

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000631 AC: 101 AN: 159948 Hom.: 1 AF XY: 0.000457 AC XY: 39 AN XY: 85370

Gnomad AFR exome AF: 0.00884

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.000953

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000320

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000291 AC: 409 AN: 1404638 Hom.: 2 Cov.: 35 AF XY: 0.000261 AC XY: 181 AN XY: 693102

Gnomad4 AFR exome AF: 0.00926

Gnomad4 AMR exome AF: 0.000413

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000250

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000102

Gnomad4 OTH exome AF: 0.000860

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152160 Hom.: 0 Cov.: 34 AF XY: 0.00245 AC XY: 182 AN XY: 74384

Gnomad4 AFR AF: 0.00845

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000761 Hom.: 0

Bravo AF: 0.00251

ESP6500AA AF: 0.00640 AC: 27

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000491 AC: 56

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Benign:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Benign:1 Other:2

other, criteria provided, single submitter	clinical testing	Invitae	Aug 11, 2018	- pseudodeficiency allele
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. -
not provided, no classification provided	literature only	GeneReviews	-	Pseudodeficiency variants -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hurler syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

May 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	30
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.074	T;T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.94
MVP		1.0
MPC		0.97
ClinPred		0.068	T
GERP RS		5.2
Varity_R		0.93
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs76722191; hg19: chr4-995942;