1-39841913-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017646.6(TRIT1):c.1235C>T(p.Ala412Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000392 in 1,605,466 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A412A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (1 hom.)
• Consequence: TRIT1 NM_017646.6 missense, splice_region
• Scores: Splicing: ADA: 0.9949
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.93

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIT1	NM_017646.6	c.1235C>T	p.Ala412Val	missense_variant, splice_region_variant	11/11	ENST00000316891.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIT1	ENST00000316891.10	c.1235C>T	p.Ala412Val	missense_variant, splice_region_variant	11/11	1	NM_017646.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152060 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000874 AC: 21 AN: 240382 Hom.: 0 AF XY: 0.0000692 AC XY: 9 AN XY: 129972

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.000177

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000461

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000372 AC: 54 AN: 1453288 Hom.: 1 Cov.: 30 AF XY: 0.0000387 AC XY: 28 AN XY: 722688

Gnomad4 AFR exome AF: 0.0000911

Gnomad4 AMR exome AF: 0.000141

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000238

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74408

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TRIT1-related conditions. This variant is present in population databases (rs147582410, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 412 of the TRIT1 protein (p.Ala412Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;.;N;N;D
REVEL	Benign	0.22
Sift	Benign	0.28	T;.;T;T;D
Sift4G	Uncertain	0.0050	D;T;T;T;D
Polyphen		0.99, 0.89, 0.98	.;D;P;D;.
Vest4		0.51
MVP		0.74
MPC		0.88
ClinPred		0.087	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.010		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: rs147582410; hg19: chr1-40307585; COSMIC: COSV105885119; COSMIC: COSV105885119;