rs1047420796

Variant names:

• chr1-39847258-C-T
• rs1047420796
• NM_017646.6:c.968G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_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 Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: TRIT1 NM_017646.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.64
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation deficiency 35

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• 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 [Likely_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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIT1	NM_017646.6	c.968G>A	p.Arg323Gln	missense_variant	Exon 8 of 11	ENST00000316891.10	NP_060116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIT1	ENST00000316891.10	c.968G>A	p.Arg323Gln	missense_variant	Exon 8 of 11	1	NM_017646.6	ENSP00000321810.5
TRIT1	ENST00000462797.5	n.968G>A		non_coding_transcript_exon_variant	Exon 8 of 10	5		ENSP00000473773.1
TRIT1	ENST00000489945.5	n.*386G>A		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000473745.1
TRIT1	ENST00000492612.6	n.*390G>A		non_coding_transcript_exon_variant	Exon 7 of 9	5		ENSP00000473708.1
TRIT1	ENST00000489945.5	n.*386G>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000473745.1
TRIT1	ENST00000492612.6	n.*390G>A		3_prime_UTR_variant	Exon 7 of 9	5		ENSP00000473708.1
TRIT1	ENST00000372818.5	c.928+290G>A		intron_variant	Intron 7 of 9	1		ENSP00000361905.1
TRIT1	ENST00000486825.6	n.*628G>A		downstream_gene_variant		5		ENSP00000474151.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251384 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined oxidative phosphorylation deficiency 35 Pathogenic:3

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Feb 19, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Pathogenic:1

Aug 18, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 31, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	.;.;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.1	.;.;M
PhyloP100		4.6
PrimateAI	Uncertain	0.50	T
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	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.71
gMVP		0.60
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1047420796; hg19: chr1-40312930; COSMIC: COSV105157813; COSMIC: COSV105157813;