rs76722191

Positions:

chr4-1002154-T-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP3BP4_ModerateBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00029 ( 2 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: 4.78

Variant links:

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]

IDUA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

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.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.965T>A	p.Val322Glu	missense_variant	7/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.965T>A	p.Val322Glu	missense_variant	7/14	2	NM_000203.5	ENSP00000425081	P1	P35475-1
IDUA	ENST00000247933.9 linkuse as main transcript	c.965T>A	p.Val322Glu	missense_variant	7/14	1		ENSP00000247933	P1	P35475-1
IDUA	ENST00000514698.5 linkuse as main transcript	n.965T>A		non_coding_transcript_exon_variant	5/11	5
IDUA	ENST00000652070.1 linkuse as main transcript	n.1021T>A		non_coding_transcript_exon_variant	6/13

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152042

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000457

AC XY:

AN XY:

85370

show subpopulations

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.:

Cov.:

AF XY:

0.000261

AC XY:

181

AN XY:

693102

show subpopulations

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.:

Cov.:

AF XY:

0.00245

AC XY:

182

AN XY:

74384

show subpopulations

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.:

Bravo

AF:

0.00251

ESP6500AA

AF:

0.00640

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000491

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Benign:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Benign:1Other:2

other, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 11, 2018	- pseudodeficiency allele
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. -

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;.

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.074

T;T

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

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

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

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