14-60975158-G-A

Position:

• chr14-60975158-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_020810.3(TRMT5):​c.1481C>T​(p.Thr494Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,607,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T494T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: TRMT5 NM_020810.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 3.06

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043415725).
• BP6: Variant 14-60975158-G-A is Benign according to our data. Variant chr14-60975158-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 692099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT5	NM_020810.3	c.1481C>T	p.Thr494Met	missense_variant	5/5	ENST00000261249.7
TRMT5	NM_001350253.1	c.1565C>T	p.Thr522Met	missense_variant	5/5
TRMT5	NM_001350254.1	c.1562C>T	p.Thr521Met	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT5	ENST00000261249.7	c.1481C>T	p.Thr494Met	missense_variant	5/5	1	NM_020810.3	P1

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00944

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000732 AC: 180 AN: 246018 Hom.: 0 AF XY: 0.000736 AC XY: 98 AN XY: 133176

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00716

Gnomad SAS exome AF: 0.000573

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.0000713

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000266 AC: 387 AN: 1455072 Hom.: 0 Cov.: 30 AF XY: 0.000298 AC XY: 216 AN XY: 723794

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000490

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00541

Gnomad4 SAS exome AF: 0.000872

Gnomad4 FIN exome AF: 0.000507

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000466

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00946

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000484

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.00520 AC: 18 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined oxidative phosphorylation defect type 26 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Pediatric Research, Children's Hospital of Soochow University, Soochow University

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

TRMT5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.82	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.078
Sift	Uncertain	0.012	D
Sift4G	Benign	0.078	T
Vest4		0.32
MVP		0.26
MPC		0.17
ClinPred		0.038	T
GERP RS		3.2
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs114570574; hg19: chr14-61441876;