1-39883469-C-G

Position:

• chr1-39883469-C-G

Variant summary

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

The NM_017646.6(TRIT1):​c.23G>C​(p.Arg8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIT1 NM_017646.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.983

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIT1	NM_017646.6	c.23G>C	p.Arg8Pro	missense_variant	1/11	ENST00000316891.10	NP_060116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIT1	ENST00000316891.10	c.23G>C	p.Arg8Pro	missense_variant	1/11	1	NM_017646.6	ENSP00000321810.5
TRIT1	ENST00000372818.5	c.23G>C	p.Arg8Pro	missense_variant	1/10	1		ENSP00000361905.1
TRIT1	ENST00000462797.5	n.23G>C		non_coding_transcript_exon_variant	1/10	5		ENSP00000473773.1
TRIT1	ENST00000486825.6	n.5G>C		non_coding_transcript_exon_variant	1/8	5		ENSP00000474151.1
TRIT1	ENST00000489945.5	n.23G>C		non_coding_transcript_exon_variant	1/7	5		ENSP00000473745.1
TRIT1	ENST00000492612.6	n.11G>C		non_coding_transcript_exon_variant	1/9	5		ENSP00000473708.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation deficiency 35 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Jun 22, 2023

The missense variant c.23G>C (p.Arg8Pro) in the TRIT1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in the gnomAD Exomes. The amino acid Arg at position 8 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg8Pro in TRIT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.79	.;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0080	.;D;D
Sift4G	Benign	0.071	T;D;D
Polyphen		1.0	D;D;.
Vest4		0.65
MutPred		0.47		Loss of MoRF binding (P = 0.0015);Loss of MoRF binding (P = 0.0015);Loss of MoRF binding (P = 0.0015);
MVP		0.75
MPC		1.1
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.32
gMVP		0.69

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

Other links and lift over

dbSNP: rs771619860; hg19: chr1-40349141; COSMIC: COSV57547593; COSMIC: COSV57547593;