1-39841869-T-C

Variant names:

• chr1-39841869-T-C
• NM_017646.6:c.1279A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017646.6(TRIT1):​c.1279A>G​(p.Arg427Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Synonymous variant affecting the same amino acid position (i.e. R427R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIT1 NM_017646.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19090143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIT1	NM_017646.6	c.1279A>G	p.Arg427Gly	missense_variant	Exon 11 of 11	ENST00000316891.10	NP_060116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIT1	ENST00000316891.10	c.1279A>G	p.Arg427Gly	missense_variant	Exon 11 of 11	1	NM_017646.6	ENSP00000321810.5
TRIT1	ENST00000372818.5	c.1201A>G	p.Arg401Gly	missense_variant	Exon 10 of 10	1		ENSP00000361905.1
TRIT1	ENST00000462797.5	n.*119A>G		non_coding_transcript_exon_variant	Exon 10 of 10	5		ENSP00000473773.1
TRIT1	ENST00000462797.5	n.*119A>G		3_prime_UTR_variant	Exon 10 of 10	5		ENSP00000473773.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 427 of the TRIT1 protein (p.Arg427Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TRIT1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TRIT1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;.;T;.;.
Eigen	Benign	0.064
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	.;.;L;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.6	D;.;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D;.;D;D;D
Sift4G	Uncertain	0.0080	D;D;T;T;D
Polyphen		0.72, 0.38, 0.29	.;P;B;B;.
Vest4		0.33
MutPred		0.32		.;.;Loss of stability (P = 0.0103);.;.;
MVP		0.63
MPC		0.67
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-40307541;