20-5942472-G-A

Position:

• chr20-5942472-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015939.5(TRMT6):​c.982C>T​(p.Pro328Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TRMT6 NM_015939.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.245

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]

TRMT6 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042826086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT6	NM_015939.5	c.982C>T	p.Pro328Ser	missense_variant	7/11	ENST00000203001.7	NP_057023.2
TRMT6	NM_001281467.2	c.472C>T	p.Pro158Ser	missense_variant	6/10		NP_001268396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT6	ENST00000203001.7	c.982C>T	p.Pro328Ser	missense_variant	7/11	1	NM_015939.5	ENSP00000203001.2
TRMT6	ENST00000453074.6	c.472C>T	p.Pro158Ser	missense_variant	6/10	2		ENSP00000392070.2
TRMT6	ENST00000466974.5	n.1054C>T		non_coding_transcript_exon_variant	7/9	2
TRMT6	ENST00000473131.5	n.1213C>T		non_coding_transcript_exon_variant	7/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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 07, 2024

The c.982C>T (p.P328S) alteration is located in exon 7 (coding exon 7) of the TRMT6 gene. This alteration results from a C to T substitution at nucleotide position 982, causing the proline (P) at amino acid position 328 to be replaced by a serine (S). 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	0.074
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.4
DANN	Benign	0.91
DEOGEN2	Benign	0.0053	T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.059
Sift	Benign	0.13	T;D
Sift4G	Benign	0.51	T;T
Polyphen		0.040	B;.
Vest4		0.054
MutPred		0.17		Gain of phosphorylation at P328 (P = 0.0191);.;
MVP		0.24
MPC		0.32
ClinPred		0.061	T
GERP RS		3.2
Varity_R		0.021
gMVP		0.27

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: rs1231605667; hg19: chr20-5923118;