rs184469579

chr1-39883470-G-Achr1-39883470-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017646.6(TRIT1):c.22C>T(p.Arg8Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,595,902 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: TRIT1 NM_017646.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 0.669

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:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 21 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-39883470-G-A is Pathogenic according to our data. Variant chr1-39883470-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-39883470-G-A is described in Lovd as [Pathogenic]. Variant chr1-39883470-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIT1	NM_017646.6	c.22C>T	p.Arg8Ter	stop_gained	1/11	ENST00000316891.10
MYCL-AS1	NR_183424.1	n.272+49G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIT1	ENST00000316891.10	c.22C>T	p.Arg8Ter	stop_gained	1/11	1	NM_017646.6	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000173 AC: 42 AN: 242456 Hom.: 0 AF XY: 0.000196 AC XY: 26 AN XY: 132626

Gnomad AFR exome AF: 0.000134

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: 0.000569

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.000353 AC: 510 AN: 1443732 Hom.: 0 Cov.: 32 AF XY: 0.000333 AC XY: 238 AN XY: 714352

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000929

Gnomad4 NFE exome AF: 0.000394

Gnomad4 OTH exome AF: 0.000388

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000911 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 12, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 417684). This premature translational stop signal has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 28185376, 34052969). This variant is present in population databases (rs184469579, gnomAD 0.06%). This sequence change creates a premature translational stop signal (p.Arg8*) 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2022	Identified in trans with a missense variant, in siblings with neurological disease in published literature (Kernohan et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28185376, 32948376, 36049610, 36047296, 34052969) -

Combined oxidative phosphorylation deficiency 35 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 16, 2018	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Likely Pathogenic, for Combined oxidative phosphorylation deficiency 35, autosomal recessive. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting. PVS1-Strong => PVS1 downgraded in strength to Strong. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/28185376). -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2022

The c.22C>T (p.R8*) alteration, located in exon 1 (coding exon 1) of the TRIT1 gene, consists of a C to T substitution at nucleotide position 22. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 8. The predicted stop codon occurs within the first 150 nucleotides of the TRIT1 gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). However, the impacted region is critical for protein function (Ambry internal data). This variant has been confirmed in trans with another TRIT1 variant in two siblings with acquired microcephaly and seizures (Kernohan, 2017). Based on internal structural analysis, the N-terminal residues 1-56 of TRIT1 contain a mitochrondrial targeting sequence which is critical to full function of the protein (Yarham, 2014; Khalique, 2020). Based on the available evidence, this alteration is classified as likely pathogenic. -

TRIT1 Deficiency Uncertain:1

Uncertain significance, no assertion criteria provided

research

Care4Rare-SOLVE, CHEO

-

This variant was seen in a heterozygous state with c.856A>G. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.059
FATHMM_MKL	Benign	0.51	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.26
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: rs184469579; hg19: chr1-40349142;