20-5946418-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015939.5(TRMT6):c.244G>A(p.Glu82Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRMT6 NM_015939.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.19

Genes affected

TRMT6 (HGNC:20900): (tRNA methyltransferase 6 non-catalytic subunit) This gene encodes a member of the tRNA methyltransferase 6 protein family. A similar protein in yeast is part of a two component methyltransferase, which is involved in the posttranslational modification that produces the modified nucleoside 1-methyladenosine in tRNAs. Modified 1-methyladenosine influences initiator methionine stability and may be involved in the replication of human immunodeficiency virus type 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26482832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT6	NM_015939.5	c.244G>A	p.Glu82Lys	missense_variant	2/11	ENST00000203001.7
TRMT6	NM_001281467.2	c.-157G>A		5_prime_UTR_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT6	ENST00000203001.7	c.244G>A	p.Glu82Lys	missense_variant	2/11	1	NM_015939.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.244G>A (p.E82K) alteration is located in exon 2 (coding exon 2) of the TRMT6 gene. This alteration results from a G to A substitution at nucleotide position 244, causing the glutamic acid (E) at amino acid position 82 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.010	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Benign	0.46	T
Sift4G	Benign	0.57	T
Polyphen		0.87	P
Vest4		0.39
MutPred		0.48		Loss of ubiquitination at K79 (P = 0.0193);
MVP		0.38
MPC		0.37
ClinPred		0.67	D
GERP RS		5.5
Varity_R		0.20
gMVP		0.50

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: rs2088707050; hg19: chr20-5927064; COSMIC: COSV52543702; COSMIC: COSV52543702;