NM_017646.6:c.334delC

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017646.6(TRIT1):c.334delC(p.Arg112GlufsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000718 in 1,609,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

TRIT1
NM_017646.6 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 3.33

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:

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-39854049-CG-C is Pathogenic according to our data. Variant chr1-39854049-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIT1	NM_017646.6 link	c.334delC	p.Arg112GlufsTer36	frameshift_variant	Exon 3 of 11	ENST00000316891.10	NP_060116.2	Q9H3H1-1Q53F11Q3T7C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRIT1	ENST00000316891.10 link	c.334delC	p.Arg112GlufsTer36	frameshift_variant	Exon 3 of 11	1	NM_017646.6	ENSP00000321810.5	Q9H3H1-1
TRIT1	ENST00000372818.5 link	c.334delC	p.Arg112GlufsTer36	frameshift_variant	Exon 3 of 10	1		ENSP00000361905.1	Q9H3H1-4
TRIT1	ENST00000462797.5 link	n.334delC		non_coding_transcript_exon_variant	Exon 3 of 10	5		ENSP00000473773.1	S4R2Z0
TRIT1	ENST00000469476.2 link	n.142delC		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000474768.1	S4R3U8
TRIT1	ENST00000486825.6 link	n.*144delC		non_coding_transcript_exon_variant	Exon 4 of 8	5		ENSP00000474151.1	S4R3C5
TRIT1	ENST00000489945.5 link	n.334delC		non_coding_transcript_exon_variant	Exon 3 of 7	5		ENSP00000473745.1	B4DK89
TRIT1	ENST00000492612.6 link	n.322delC		non_coding_transcript_exon_variant	Exon 3 of 9	5		ENSP00000473708.1	S4R2X1
TRIT1	ENST00000486825.6 link	n.*144delC		3_prime_UTR_variant	Exon 4 of 8	5		ENSP00000474151.1	S4R3C5

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000427

AC:

106

AN:

248326

Hom.:

AF XY:

0.000484

AC XY:

AN XY:

134270

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000705

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000691

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000758

AC:

1105

AN:

1457762

Hom.:

Cov.:

AF XY:

0.000736

AC XY:

534

AN XY:

725380

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000549

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000923

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000335

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000564

Hom.:

Bravo

AF:

0.000408

EpiCase

AF:

0.000327

EpiControl

AF:

0.00101

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRIT1: PVS1, PM2 -

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg112Glufs*36) 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 (rs536000212, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with epilepsy (PMID: 30977854). ClinVar contains an entry for this variant (Variation ID: 545453). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Epileptic encephalopathy

Pathogenic:1

Jun 01, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases

Pathogenic:1

Apr 02, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1, PS4, PM2, PM3 -

TRIT1 Deficiency

Pathogenic:1

Feb 05, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.334del;p.(Arg112Glufs*36) is a null frameshift variant (NMD) in the TRIT1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. The variant is present at low allele frequencies population databases (rs536000212– gnomAD 0.003353%; ABraOM 0.001281 frequency - http://abraom.ib.usp.br/) -PM2_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Combined oxidative phosphorylation deficiency 35

Pathogenic:1

Feb 05, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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