rs746738473

Positions:

• chr14-60976047-C-A
• chr14-60976047-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020810.3(TRMT5):​c.872G>T​(p.Arg291Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRMT5 NM_020810.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50

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]

ENSG00000258892 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT5	NM_020810.3	c.872G>T	p.Arg291Leu	missense_variant	4/5	ENST00000261249.7	NP_065861.3
TRMT5	NM_001350253.1	c.956G>T	p.Arg319Leu	missense_variant	4/5		NP_001337182.1
TRMT5	NM_001350254.1	c.953G>T	p.Arg318Leu	missense_variant	4/5		NP_001337183.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT5	ENST00000261249.7	c.872G>T	p.Arg291Leu	missense_variant	4/5	1	NM_020810.3	ENSP00000261249.6
ENSG00000258892	ENST00000553946.1	n.123-6461C>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.33	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Vest4		0.97
MutPred		0.80		Gain of catalytic residue at E294 (P = 0.0113);
MVP		0.74
MPC		0.51
ClinPred		1.0	D
GERP RS		5.8
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs746738473; hg19: chr14-61442765;