rs536000212

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_017646.6(TRIT1):c.334delC(p.Arg112GlufsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000718 in 1,609,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

TRIT1
NM_017646.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.33

Publications

4 publications found

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 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

TRIT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 1-39854049-CG-C is Pathogenic according to our data. Variant chr1-39854049-CG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 545453.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 link	c.334delC	p.Arg112GlufsTer36	frameshift_variant	Exon 3 of 11	ENST00000316891.10	NP_060116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TRIT1	ENST00000316891.10 link	c.334delC	p.Arg112GlufsTer36	frameshift_variant	Exon 3 of 11	1	NM_017646.6	ENSP00000321810.5
TRIT1	ENST00000372818.5 link	c.334delC	p.Arg112GlufsTer36	frameshift_variant	Exon 3 of 10	1		ENSP00000361905.1
TRIT1	ENST00000462797.5 link	n.334delC		non_coding_transcript_exon_variant	Exon 3 of 10	5		ENSP00000473773.1
TRIT1	ENST00000469476.2 link	n.142delC		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000474768.1
TRIT1	ENST00000486825.6 link	n.*144delC		non_coding_transcript_exon_variant	Exon 4 of 8	5		ENSP00000474151.1
TRIT1	ENST00000489945.5 link	n.334delC		non_coding_transcript_exon_variant	Exon 3 of 7	5		ENSP00000473745.1
TRIT1	ENST00000492612.6 link	n.322delC		non_coding_transcript_exon_variant	Exon 3 of 9	5		ENSP00000473708.1
TRIT1	ENST00000486825.6 link	n.*144delC		3_prime_UTR_variant	Exon 4 of 8	5		ENSP00000474151.1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000427

AC:

106

AN:

248326

AF XY:

0.000484

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000691

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000758

AC:

1105

AN:

1457762

Hom.:

Cov.:

AF XY:

0.000736

AC XY:

534

AN XY:

725380

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33302

American (AMR)

AF:

0.000159

AC:

AN:

44040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.000549

AC:

AN:

85582

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000923

AC:

1025

AN:

1110008

Other (OTH)

AF:

0.000398

AC:

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000335

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41538

American (AMR)

AF:

0.000262

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00145

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000564

Hom.:

Bravo

AF:

0.000408

EpiCase

AF:

0.000327

EpiControl

AF:

0.00101

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Dec 04, 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.Arg112Glufs*36) 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 (rs536000212, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with epilepsy (PMID: 30977854). ClinVar contains an entry for this variant (Variation ID: 545453). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRIT1: PVS1, PM2

Combined oxidative phosphorylation deficiency 35

Pathogenic:2

Feb 05, 2024

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

May 11, 2023

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PVS1 very strong, PM3 moderate

Epileptic encephalopathy

Pathogenic:1

Jun 01, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See cases

Pathogenic:1

Apr 02, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PVS1, PS4, PM2, PM3

TRIT1 Deficiency

Pathogenic:1

Feb 05, 2022

DASA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.334del;p.(Arg112Glufs*36) is a null frameshift variant (NMD) in the TRIT1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. The variant is present at low allele frequencies population databases (rs536000212– gnomAD 0.003353%; ABraOM 0.001281 frequency - http://abraom.ib.usp.br/) -PM2_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over