1-39883470-G-A

Position:

chr1-39883470-G-A

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.Arg8Ter) 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

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

TRIT1
NM_017646.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 0.669

Variant links:

Genes affected

TRIT1 (HGNC:20286): (tRNA isopentenyltransferase 1) This gene encodes a protein that that is targeted to the mitochondrion and modifies transfer RNAs (tRNAs) by adding a dimethylallyl group onto the adenine at position 37. This modification is important for maintaining the correct reading frame during protein translation. This gene is considered a tumor suppressor and its expression can decrease cell growth. Alternative splicing results in multiple transcripts variants, most of which are likely non-functional. [provided by RefSeq, Aug 2015]

TRIT1 links:

MYCL-AS1 (HGNC:):

MYCL-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-39883470-G-A is Pathogenic according to our data. Variant chr1-39883470-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-39883470-G-A is described in Lovd as [Pathogenic]. Variant chr1-39883470-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIT1	NM_017646.6 linkuse as main transcript	c.22C>T	p.Arg8Ter	stop_gained	1/11	ENST00000316891.10
MYCL-AS1	NR_183424.1 linkuse as main transcript	n.272+49G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIT1	ENST00000316891.10 linkuse as main transcript	c.22C>T	p.Arg8Ter	stop_gained	1/11	1	NM_017646.6	P1	Q9H3H1-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000173

AC:

AN:

242456

Hom.:

AF XY:

0.000196

AC XY:

AN XY:

132626

show subpopulations

Gnomad AFR exome

AF:

0.000134

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000569

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.000511

GnomAD4 exome

AF:

0.000353

AC:

510

AN:

1443732

Hom.:

Cov.:

AF XY:

0.000333

AC XY:

238

AN XY:

714352

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000929

Gnomad4 NFE exome

AF:

0.000394

Gnomad4 OTH exome

AF:

0.000388

GnomAD4 genome

AF:

0.000164

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000911

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation deficiency 35

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 16, 2018	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 08, 2023	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 12, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 417684). This premature translational stop signal has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 28185376, 34052969). This variant is present in population databases (rs184469579, gnomAD 0.06%). 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2022	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2022

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

Uncertain significance, no assertion criteria provided

research

Care4Rare-SOLVE, CHEO

This variant was seen in a heterozygous state with c.856A>G. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.059

FATHMM_MKL

Benign

0.51

MutationTaster

Benign

1.0

A;A;A;A;A

Vest4

0.26

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over