chr4-987095-T-C

Position:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000203.5(IDUA):ā€‹c.11T>Cā€‹(p.Leu4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000731 in 1,470,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.00063 ( 0 hom., cov: 33)
Exomes š‘“: 0.00074 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

1
3
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -4.71
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.027771503).
BP6
Variant 4-987095-T-C is Benign according to our data. Variant chr4-987095-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526832.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IDUANM_000203.5 linkuse as main transcriptc.11T>C p.Leu4Pro missense_variant 1/14 ENST00000514224.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IDUAENST00000514224.2 linkuse as main transcriptc.11T>C p.Leu4Pro missense_variant 1/142 NM_000203.5 P1P35475-1

Frequencies

GnomAD3 genomes
AF:
0.000632
AC:
96
AN:
152004
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.000577
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00637
Gnomad NFE
AF:
0.000956
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000512
AC:
49
AN:
95626
Hom.:
1
AF XY:
0.000380
AC XY:
21
AN XY:
55198
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000431
Gnomad ASJ exome
AF:
0.00204
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000677
Gnomad OTH exome
AF:
0.000417
GnomAD4 exome
AF:
0.000743
AC:
979
AN:
1318046
Hom.:
0
Cov.:
30
AF XY:
0.000712
AC XY:
464
AN XY:
651554
show subpopulations
Gnomad4 AFR exome
AF:
0.0000747
Gnomad4 AMR exome
AF:
0.000716
Gnomad4 ASJ exome
AF:
0.00176
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000829
Gnomad4 OTH exome
AF:
0.000871
GnomAD4 genome
AF:
0.000631
AC:
96
AN:
152112
Hom.:
0
Cov.:
33
AF XY:
0.000645
AC XY:
48
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.000577
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000957
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000529
Hom.:
0
Bravo
AF:
0.000797
ExAC
AF:
0.000163
AC:
16
Asia WGS
AF:
0.000290
AC:
1
AN:
3458

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1 Uncertain:1Benign:2
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Jun 01, 2020- -
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityApr 02, 2020- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 02, 2022This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.030
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
2.0
DANN
Benign
0.53
DEOGEN2
Benign
0.18
T;.
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.015
N
LIST_S2
Benign
0.34
T;T
M_CAP
Pathogenic
0.68
D
MetaRNN
Benign
0.028
T;T
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Benign
-1.7
N;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
0.35
N;N
REVEL
Uncertain
0.34
Sift
Benign
0.23
T;T
Sift4G
Benign
0.23
T;T
Polyphen
0.0
B;.
Vest4
0.099
MVP
0.42
MPC
0.30
ClinPred
0.017
T
GERP RS
-2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.047
gMVP
0.74

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

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

Other links and lift over

dbSNP: rs180984980; hg19: chr4-980883; API