rs755184077

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_020810.3(TRMT5):c.312_315delAATA(p.Ile105SerfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.000902 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 0 hom. )

Consequence

TRMT5
NM_020810.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:3

Conservation

PhyloP100: 6.82

Publications

7 publications found

Variant links:

Genes affected

TRMT5 (HGNC:23141): (tRNA methyltransferase 5) tRNAs contain as many as 13 or 14 nucleotides that are modified posttranscriptionally by enzymes that are highly specific for particular nucleotides in the tRNA structure. TRMT5 methylates the N1 position of guanosine-37 (G37) in selected tRNAs using S-adenosyl methionine (Brule et al., 2004 [PubMed 15248782]).[supplied by OMIM, Mar 2008]

TRMT5 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
combined oxidative phosphorylation defect type 26
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

TRMT5 links:

ENSG00000258892 (HGNC:):

ENSG00000258892 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

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

PP5

Variant 14-60979582-CTATT-C is Pathogenic according to our data. Variant chr14-60979582-CTATT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372246.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMT5	NM_020810.3 link	c.312_315delAATA	p.Ile105SerfsTer4	frameshift_variant	Exon 2 of 5	ENST00000261249.7	NP_065861.3	Q32P41
TRMT5	NM_001350253.1 link	c.396_399delAATA	p.Ile133SerfsTer4	frameshift_variant	Exon 2 of 5		NP_001337182.1
TRMT5	NM_001350254.1 link	c.393_396delAATA	p.Ile132SerfsTer4	frameshift_variant	Exon 2 of 5		NP_001337183.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRMT5	ENST00000261249.7 link	c.312_315delAATA	p.Ile105SerfsTer4	frameshift_variant	Exon 2 of 5	1	NM_020810.3	ENSP00000261249.6	Q32P41
TRMT5	ENST00000553903.1 link	c.396_399delAATA	p.Ile133SerfsTer4	frameshift_variant	Exon 2 of 2	4		ENSP00000452567.1	G3V5X1
TRMT5	ENST00000555420.1 link	c.393_396delAATA	p.Ile132SerfsTer4	frameshift_variant	Exon 2 of 2	4		ENSP00000451666.1	G3V494
ENSG00000258892	ENST00000553946.1 link	n.123-2924_123-2921delATTT		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.000821

AC:

125

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000867

AC:

218

AN:

251378

AF XY:

0.000979

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00337

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00130

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000910

AC:

1331

AN:

1461868

Hom.:

AF XY:

0.000873

AC XY:

635

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00291

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000383

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00102

AC:

1132

AN:

1112000

Other (OTH)

AF:

0.000993

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

165

247

330

412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<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:

0.000821

AC:

125

AN:

152282

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41562

American (AMR)

AF:

0.000589

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00135

AC:

AN:

68028

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000473

Hom.:

Bravo

AF:

0.000733

EpiCase

AF:

0.00153

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:2

Sep 14, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 31038196, 26189817, 29021354, 35342985) -

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ile105Serfs*4) in the TRMT5 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TRMT5 cause disease. This variant is present in population databases (rs755184077, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with features of combined oxidative phosphorylation deficiency (PMID: 26189817, 29021354). ClinVar contains an entry for this variant (Variation ID: 372246). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRMT5: PS4, PM4 -

Jul 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Combined oxidative phosphorylation defect type 26

Pathogenic:3

Jun 01, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 15, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

TRMT5-related disorder

Pathogenic:1

Sep 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TRMT5 c.312_315delAATA variant is predicted to result in a frameshift and premature protein termination (p.Ile105Serfs*4). This variant was previously described in the presumably compound heterozygous state in two unrelated individuals who presented with combined oxidative phosphorylation deficiency (Powell et al. 2015. PubMed ID: 26189817), and in the compound heterozygous state in two affected sisters from a different family (Tamopolsky et al. 2017. PubMed ID: 29021354). The c.312_315del variant has a relatively high minor allele frequency (~0.33%) in at least one sub-population in a large population database, but no homozygotes were described in the same database. Frameshift variants in TRMT5 are expected to be pathogenic. This variant is classified as likely pathogenic. -

not specified

Uncertain:1

Mar 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TRMT5 c.312_315delAATA (p.Ile105SerfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The tRNA methyltransferase 5 (TRMT5) gene encodes a protein involved in methylation of a specific nucleotide (position 37) adjacent to the anticodon of mitochondrial-tRNA molecules to enhance their translational efficiency/fidelity (Tarnopolsky_2017). The p.Ile105Serfs*4 frameshift mutation is upstream of the methyltransferase motif, therefore it is predicted to result in a truncated protein that is expected to be non-functional (Powell_2015). The variant allele was found at a frequency of 0.00087 in 251378 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. As the prevalence of Combined Oxidative Phosphorylation Defect Type 26 and attributable risk of TRMT5 gene and variants cannot be estimated, this frequency does not allow conclusions about variant significance. c.312_315delAATA has been reported in the literature as a compound heterozygous genotype with other TRMT5 missense variants in trans in at least seven probands from six separate families presenting with varying clinical features, suggestive of mitochondrial disease (e.g., Powell_2015, Tarnopolsky_2017, Argente-Escrig_2022). Each of these probands were comprehensively evaluated to rule out other genetic conditions prior to whole exome sequencing (WES). It has also been reported as a non-informative genotype (zygosity/genotype not specified) in an autistic proband who underwent whole genome sequencing (e.g., Callaghan_2019) but has not been considered as a relevant correlation in the context of this evaluation. These data indicate that the variant might be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 372246). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.8

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

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

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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