chr1-39883476-C-T

Position:

chr1-39883476-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017646.6(TRIT1):c.16G>A(p.Ala6Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000846 in 1,596,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 0 hom. )

Consequence

TRIT1
NM_017646.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.02

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042782456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIT1	NM_017646.6 linkuse as main transcript	c.16G>A	p.Ala6Thr	missense_variant	1/11	ENST00000316891.10
MYCL-AS1	NR_183424.1 linkuse as main transcript	n.272+55C>T		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.16G>A	p.Ala6Thr	missense_variant	1/11	1	NM_017646.6	P1	Q9H3H1-1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000429

AC:

105

AN:

244576

Hom.:

AF XY:

0.000443

AC XY:

AN XY:

133112

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000587

Gnomad ASJ exome

AF:

0.000203

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000703

Gnomad OTH exome

AF:

0.000671

GnomAD4 exome

AF:

0.000887

AC:

1280

AN:

1443758

Hom.:

Cov.:

AF XY:

0.000851

AC XY:

608

AN XY:

714178

show subpopulations

Gnomad4 AFR exome

AF:

0.0000907

Gnomad4 AMR exome

AF:

0.000588

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.000640

GnomAD4 genome

AF:

0.000459

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000667

Hom.:

Bravo

AF:

0.000597

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000429

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.000653

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The c.16G>A (p.A6T) alteration is located in exon 1 (coding exon 1) of the TRIT1 gene. This alteration results from a G to A substitution at nucleotide position 16, causing the alanine (A) at amino acid position 6 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 6 of the TRIT1 protein (p.Ala6Thr). This variant is present in population databases (rs138415849, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TRIT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1365813). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Combined oxidative phosphorylation deficiency 35

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

.;T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

0.0086

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;N

MutationTaster

Benign

0.99

N;N;N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.23

.;N;N

REVEL

Benign

0.089

Sift

Benign

0.055

.;T;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.029

B;B;.

Vest4

0.53

MVP

0.65

MPC

0.37

ClinPred

0.11

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.080

gMVP

0.50

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