rs536000212

chr1-39854049-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017646.6(TRIT1):c.334del(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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.33

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]

ACMG classification

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/exons	MANE	UniProt
TRIT1	NM_017646.6	c.334del	p.Arg112GlufsTer36	frameshift_variant	3/11	ENST00000316891.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIT1	ENST00000316891.10	c.334del	p.Arg112GlufsTer36	frameshift_variant	3/11	1	NM_017646.6	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152104 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000484 AC XY: 65 AN XY: 134270

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.: 0 Cov.: 29 AF XY: 0.000736 AC XY: 534 AN XY: 725380

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: 51 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74426

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.: 0

Bravo AF: 0.000408

EpiCase AF: 0.000327

EpiControl AF: 0.00101

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jun 01, 2017

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Apr 02, 2020

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

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

TRIT1: PVS1, PM2 -

TRIT1 Deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

DASA

Feb 05, 2022

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs536000212; hg19: chr1-40319721;