20-5941979-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015939.5(TRMT6):c.1084G>A(p.Ala362Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TRMT6 NM_015939.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.095724314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT6	NM_015939.5	c.1084G>A	p.Ala362Thr	missense_variant	8/11	ENST00000203001.7
TRMT6	NM_001281467.2	c.574G>A	p.Ala192Thr	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT6	ENST00000203001.7	c.1084G>A	p.Ala362Thr	missense_variant	8/11	1	NM_015939.5	P1
TRMT6	ENST00000453074.6	c.574G>A	p.Ala192Thr	missense_variant	7/10	2
TRMT6	ENST00000466974.5	n.1156G>A		non_coding_transcript_exon_variant	8/9	2
TRMT6	ENST00000473131.5	n.1315G>A		non_coding_transcript_exon_variant	8/11	5

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251006 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461148 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 726912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74492

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.000181

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

May 25, 2022

The c.1084G>A (p.A362T) alteration is located in exon 8 (coding exon 8) of the TRMT6 gene. This alteration results from a G to A substitution at nucleotide position 1084, causing the alanine (A) at amino acid position 362 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.097
Sift	Benign	0.32	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.61	P;.
Vest4		0.26
MutPred		0.57		Gain of glycosylation at A362 (P = 0.0335);.;
MVP		0.35
MPC		0.30
ClinPred		0.12	T
GERP RS		4.2
Varity_R		0.18
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs575474127; hg19: chr20-5922625;