1-39883434-G-A

Variant names:

• chr1-39883434-G-A
• rs1316814581
• NM_017646.6:c.58C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_017646.6(TRIT1):​c.58C>T​(p.Gln20*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TRIT1 NM_017646.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.902

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]

MYCL-AS1 (HGNC:40386): (MYCL antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-39883434-G-A is Pathogenic according to our data. Variant chr1-39883434-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3605774.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIT1	NM_017646.6	c.58C>T	p.Gln20*	stop_gained	Exon 1 of 11	ENST00000316891.10	NP_060116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIT1	ENST00000316891.10	c.58C>T	p.Gln20*	stop_gained	Exon 1 of 11	1	NM_017646.6	ENSP00000321810.5
TRIT1	ENST00000372818.5	c.58C>T	p.Gln20*	stop_gained	Exon 1 of 10	1		ENSP00000361905.1
TRIT1	ENST00000462797.5	n.58C>T		non_coding_transcript_exon_variant	Exon 1 of 10	5		ENSP00000473773.1
TRIT1	ENST00000486825.6	n.40C>T		non_coding_transcript_exon_variant	Exon 1 of 8	5		ENSP00000474151.1
TRIT1	ENST00000489945.5	n.58C>T		non_coding_transcript_exon_variant	Exon 1 of 7	5		ENSP00000473745.1
TRIT1	ENST00000492612.6	n.46C>T		non_coding_transcript_exon_variant	Exon 1 of 9	5		ENSP00000473708.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248978 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461016 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln20*) in the TRIT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRIT1 are known to be pathogenic (PMID: 24901367, 28185376). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TRIT1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.098
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.41	N
Vest4		0.17
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1316814581; hg19: chr1-40349106;