rs370011798
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 ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I223M) has been classified as Uncertain significance.
Frequency
Consequence
NM_182916.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRNT1 | NM_182916.3 | c.668T>C | p.Ile223Thr | missense_variant | 6/8 | ENST00000251607.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRNT1 | ENST00000251607.11 | c.668T>C | p.Ile223Thr | missense_variant | 6/8 | 1 | NM_182916.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152166Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251240Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135808
GnomAD4 exome AF: 0.0000937 AC: 137AN: 1461698Hom.: 0 Cov.: 31 AF XY: 0.0000921 AC XY: 67AN XY: 727156
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152282Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7AN XY: 74478
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 08, 2018 | - - |
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 | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | TRNT1: PM3:Strong, PM1, PM2, PM5, PS3:Supporting - |
Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 30, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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. - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at