rs370011798
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_182916.3(TRNT1):āc.668T>Cā(p.Ile223Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ).
Frequency
Genomes: š 0.000079 ( 0 hom., cov: 31)
Exomes š: 0.000094 ( 0 hom. )
Consequence
TRNT1
NM_182916.3 missense
NM_182916.3 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 7.78
Genes affected
TRNT1 (HGNC:17341): (tRNA nucleotidyl transferase 1) The protein encoded by this gene is a CCA-adding enzyme which belongs to the tRNA nucleotidyltransferase/poly(A) polymerase family. This essential enzyme functions by catalyzing the addition of the conserved nucleotide triplet CCA to the 3' terminus of tRNA molecules. Mutations in this gene result in sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
CRBN (HGNC:30185): (cereblon) This gene encodes a protein related to the Lon protease protein family. In rodents and other mammals this gene product is found in the cytoplasm localized with a calcium channel membrane protein, and is thought to play a role in brain development. Mutations in this gene are associated with autosomal recessive nonsyndromic cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95
PP5
Variant 3-3146489-T-C is Pathogenic according to our data. Variant chr3-3146489-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 157614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TRNT1 | NM_182916.3 | c.668T>C | p.Ile223Thr | missense_variant | 6/8 | ENST00000251607.11 | NP_886552.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRNT1 | ENST00000251607.11 | c.668T>C | p.Ile223Thr | missense_variant | 6/8 | 1 | NM_182916.3 | ENSP00000251607.6 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152166Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251240Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135808
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GnomAD4 exome AF: 0.0000937 AC: 137AN: 1461698Hom.: 0 Cov.: 31 AF XY: 0.0000921 AC XY: 67AN XY: 727156
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GnomAD4 genome AF: 0.0000788 AC: 12AN: 152282Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7AN XY: 74478
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | TRNT1: PM3:Strong, PM1, PM2, PM5, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 07, 2022 | Published functional studies found this variant is associated with significantly reduced enzyme activity and stability (Leibovitch M et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29358286, 27370603, 25193871, 31555444, 31338833, 29055896, 29454993) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 08, 2018 | - - |
Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 11, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 223 of the TRNT1 protein (p.Ile223Thr). This variant is present in population databases (rs370011798, gnomAD 0.009%). This missense change has been observed in individual(s) with sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (PMID: 25193871, 27370603, 29055896, 29358286). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 157614). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRNT1 protein function. Experimental studies have shown that this missense change affects TRNT1 function (PMID: 25193871, 29454993). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 30, 2014 | - - |
TRNT1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 22, 2023 | The TRNT1 c.668T>C variant is predicted to result in the amino acid substitution p.Ile223Thr. This variant has been reported in the compound heterozygous and homozygous states in individuals with sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) (Chakraborty et al. 2014. PubMed ID: 25193871; Wedatilake et al. 2016. PubMed ID: 2737060; Barton et al. 2018. PubMed ID: 29055896; Giannelou et al. 2018. PubMed ID: 29358286; Jfri et al. 2019. PubMed ID: 31555444). Of note, in addition to the clinical features typically associated with SIFD, metabolic features and severe fetal hydrops and neonatal anemia were also reported in cases of SIFD (Wedatilake et al. 2016. PubMed ID: 2737060; Barton et al. 2018. PubMed ID: 29055896). A functional study showed that that c.668T>C (p.Ile223Thr) variant impacts protein function (Leibovitch et al. 2018. PubMed ID: 29454993). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-3188173-T-C). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at