22-20114987-G-A

Variant summary

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

The NM_022727.6(TRMT2A):c.983C>T(p.Ala328Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRMT2A NM_022727.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

Genes affected

TRMT2A (HGNC:24974): (tRNA methyltransferase 2 homolog A) The protein encoded by this gene is of unknown function. However, it is orthologous to the mouse Trmt2a gene and contains an RNA methyltransferase domain. Expression of this gene varies during the cell cycle, with aberrant expression being a possible biomarker in certain breast cancers. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

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=0.26935768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT2A	NM_022727.6	c.983C>T	p.Ala328Val	missense_variant	5/12	ENST00000252136.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT2A	ENST00000252136.12	c.983C>T	p.Ala328Val	missense_variant	5/12	1	NM_022727.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1444838 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 717046

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: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

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

Sep 25, 2023

The c.983C>T (p.A328V) alteration is located in exon 5 (coding exon 5) of the TRMT2A gene. This alteration results from a C to T substitution at nucleotide position 983, causing the alanine (A) at amino acid position 328 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	26
Dann	Benign	0.94
DEOGEN2	Benign	0.033	T;T;.;T
Eigen	Benign	-0.074
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.64	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.57
MutPred		0.56		Gain of MoRF binding (P = 0.1043);Gain of MoRF binding (P = 0.1043);Gain of MoRF binding (P = 0.1043);Gain of MoRF binding (P = 0.1043);
MVP		0.22
MPC		0.11
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.28
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs760345390; hg19: chr22-20102510;