rs1047420796

Positions:

chr1-39847258-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_017646.6(TRIT1):c.968G>A(p.Arg323Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,976 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R323W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TRIT1
NM_017646.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.64

Variant links:

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 links:

TRIT1 (HGNC:):

TRIT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a region_of_interest Interaction with substrate tRNA (size 18) in uniprot entity MOD5_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_017646.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-39847259-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1686274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 1-39847258-C-T is Pathogenic according to our data. Variant chr1-39847258-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 492943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-39847258-C-T is described in Lovd as [Pathogenic]. Variant chr1-39847258-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIT1	NM_017646.6 linkuse as main transcript	c.968G>A	p.Arg323Gln	missense_variant	8/11	ENST00000316891.10	NP_060116.2	Q9H3H1-1Q53F11Q3T7C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TRIT1	ENST00000316891.10 linkuse as main transcript	c.968G>A	p.Arg323Gln	missense_variant	8/11	1	NM_017646.6	ENSP00000321810.5	Q9H3H1-1
TRIT1	ENST00000372818.5 linkuse as main transcript	c.928+290G>A		intron_variant		1		ENSP00000361905.1	Q9H3H1-4
TRIT1	ENST00000462797.5 linkuse as main transcript	n.968G>A		non_coding_transcript_exon_variant	8/10	5		ENSP00000473773.1	S4R2Z0
TRIT1	ENST00000489945.5 linkuse as main transcript	n.*386G>A		non_coding_transcript_exon_variant	7/7	5		ENSP00000473745.1	B4DK89
TRIT1	ENST00000492612.6 linkuse as main transcript	n.*390G>A		non_coding_transcript_exon_variant	7/9	5		ENSP00000473708.1	S4R2X1
TRIT1	ENST00000489945.5 linkuse as main transcript	n.*386G>A		3_prime_UTR_variant	7/7	5		ENSP00000473745.1	B4DK89
TRIT1	ENST00000492612.6 linkuse as main transcript	n.*390G>A		3_prime_UTR_variant	7/9	5		ENSP00000473708.1	S4R2X1
TRIT1	ENST00000486825.6 linkuse as main transcript	n.*628G>A		downstream_gene_variant		5		ENSP00000474151.1	S4R3C5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251384

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation deficiency 35

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 19, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.968G>A(p.Arg323Gln) in TRIT1 gene has been reported previously in homozygous state inindividuals with Combined oxidative phosphorylation deficiency / mitochondrial disease (Whittaker RG, et al., 2015, Yarham JW, etal., 2014). The c.968G>A variant has 0.001% allele frequency in gnomAD Exomes. A different amino acid change p.Arg323Trp issubmitted to ClinVar as Pathogenic / Likely Pathogenic. This variant has been reported to the ClinVar database as Pathogenic.Theamino acid Arginine at position 323 is changed to a Glutamine changing protein sequence and it might alter its composition andphysico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and Mutation Taster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg323Gln in TRIT1 is predicted as conserved byGERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Pathogenic, for Combined oxidative phosphorylation deficiency 35, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. 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/24901367). PS3-Very Strong => PS3 upgraded in strength to Very Strong (https://www.ncbi.nlm.nih.gov/pubmed/24901367). -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2017

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2024

Reported in an adult with mitochondrial disease and epilepsy (PMID: 26381753); Expression studies in E. coli and yeast found that this variant impaired the isopentenyltransferase activity of TRIT1 (PMID: 24901367); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26857223, 28185376, 24901367, 37393059, 26381753) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

.;.;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

3.1

.;.;M

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.6

D;.;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.0050

D;.;D

Sift4G

Uncertain

0.021

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.89

MutPred

0.84

.;.;Loss of stability (P = 0.0692);

MVP

0.79

MPC

1.0

ClinPred

0.98

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.71

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over