chr1-39844110-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_017646.6(TRIT1):c.1225G>A(p.Glu409Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,160 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 Likely pathogenic (★★).
Frequency
Consequence
NM_017646.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRIT1 | ENST00000316891.10 | c.1225G>A | p.Glu409Lys | missense_variant | Exon 10 of 11 | 1 | NM_017646.6 | ENSP00000321810.5 | ||
TRIT1 | ENST00000372818.5 | c.1147G>A | p.Glu383Lys | missense_variant | Exon 9 of 10 | 1 | ENSP00000361905.1 | |||
TRIT1 | ENST00000462797.5 | n.*65G>A | non_coding_transcript_exon_variant | Exon 9 of 10 | 5 | ENSP00000473773.1 | ||||
TRIT1 | ENST00000462797.5 | n.*65G>A | 3_prime_UTR_variant | Exon 9 of 10 | 5 | ENSP00000473773.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251306Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135812
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460950Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 726862
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 409 of the TRIT1 protein (p.Glu409Lys). This variant is present in population databases (rs764506732, gnomAD 0.008%). This missense change has been observed in individual(s) with TRIT1-related conditions (PMID: 32948376). 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. This variant is also known as c.979G>A (p.Glu327Lys). ClinVar contains an entry for this variant (Variation ID: 1201174). 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 TRIT1 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36768505, Cheon (2022)_ article, 32948376) -
Combined oxidative phosphorylation deficiency 35 Pathogenic:1
The observed missense variant c.1225G>A(p.Glu409Lys) in TRIT1 gene has been reported previously in compound heterozygousstate in siblings with Combined oxidative phosphorylation deficiency (Yoo S, et al., 2021). Protein structure analysis revealed thatthis variant disrupts the conformation and electrostatic charge of the zinc-finger motif in the tRNA isopentenyltransferase (IPT),impairing binding of the mutant IPT to specific DNA sequences (Yoo S, et al., 2021).The c.1225G>A variant has 0.001% allele frequencyin gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic. Multiple lines of computationalevidence (Polyphen, SIFT and Mutation Taster) predict a damaging effect on protein structure and function for this variant. Theamino acid Glutamine at position 409 is changed to a Lysine changing protein sequence and it might alter its composition andphysico-chemical properties. The amino acid change p.Glu409Lys in TRIT1 is predicted as conserved by GERP++ and PhyloP across100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at