NM_017646.6:c.22C>T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017646.6(TRIT1):c.22C>T(p.Arg8*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,595,902 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 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRIT1 | ENST00000316891.10 | c.22C>T | p.Arg8* | stop_gained | Exon 1 of 11 | 1 | NM_017646.6 | ENSP00000321810.5 | ||
TRIT1 | ENST00000372818.5 | c.22C>T | p.Arg8* | stop_gained | Exon 1 of 10 | 1 | ENSP00000361905.1 | |||
TRIT1 | ENST00000462797.5 | n.22C>T | non_coding_transcript_exon_variant | Exon 1 of 10 | 5 | ENSP00000473773.1 | ||||
TRIT1 | ENST00000486825.6 | n.4C>T | non_coding_transcript_exon_variant | Exon 1 of 8 | 5 | ENSP00000474151.1 | ||||
TRIT1 | ENST00000489945.5 | n.22C>T | non_coding_transcript_exon_variant | Exon 1 of 7 | 5 | ENSP00000473745.1 | ||||
TRIT1 | ENST00000492612.6 | n.10C>T | non_coding_transcript_exon_variant | Exon 1 of 9 | 5 | ENSP00000473708.1 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000173 AC: 42AN: 242456Hom.: 0 AF XY: 0.000196 AC XY: 26AN XY: 132626
GnomAD4 exome AF: 0.000353 AC: 510AN: 1443732Hom.: 0 Cov.: 32 AF XY: 0.000333 AC XY: 238AN XY: 714352
GnomAD4 genome AF: 0.000164 AC: 25AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74324
ClinVar
Submissions by phenotype
Combined oxidative phosphorylation deficiency 35 Pathogenic:3
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This variant is interpreted as Likely Pathogenic, for Combined oxidative phosphorylation deficiency 35, autosomal recessive. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting. PVS1-Strong => PVS1 downgraded in strength to Strong. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/28185376). -
not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Arg8*) in the TRIT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRIT1 are known to be pathogenic (PMID: 24901367, 28185376). This variant is present in population databases (rs184469579, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 28185376, 34052969). ClinVar contains an entry for this variant (Variation ID: 417684). For these reasons, this variant has been classified as Pathogenic. -
Identified in trans with a missense variant, in siblings with neurological disease in published literature (Kernohan et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28185376, 32948376, 36049610, 36047296, 34052969) -
Inborn genetic diseases Pathogenic:1
The c.22C>T (p.R8*) alteration, located in exon 1 (coding exon 1) of the TRIT1 gene, consists of a C to T substitution at nucleotide position 22. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 8. The predicted stop codon occurs within the first 150 nucleotides of the TRIT1 gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). However, the impacted region is critical for protein function (Ambry internal data). This variant has been confirmed in trans with another TRIT1 variant in two siblings with acquired microcephaly and seizures (Kernohan, 2017). Based on internal structural analysis, the N-terminal residues 1-56 of TRIT1 contain a mitochrondrial targeting sequence which is critical to full function of the protein (Yarham, 2014; Khalique, 2020). Based on the available evidence, this alteration is classified as likely pathogenic. -
TRIT1 Deficiency Uncertain:1
This variant was seen in a heterozygous state with c.856A>G. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at