22-20116081-G-A

Variant summary

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

The NM_022727.6(TRMT2A):c.556C>T(p.Arg186Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000196 in 1,582,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TRMT2A NM_022727.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.534

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]

RANBP1 (HGNC:9847): (RAN binding protein 1) This gene encodes a protein that forms a complex with Ras-related nuclear protein (Ran) and metabolizes guanoside triphosphate (GTP). This complex participates in the regulation of the cell cycle by controlling transport of proteins and nucleic acids into the nucleus. There are multiple pseudogenes for this gene on chromosomes 9, 12, 17, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

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=0.048319727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT2A	NM_022727.6	c.556C>T	p.Arg186Trp	missense_variant	2/12	ENST00000252136.12
RANBP1	NM_001278639.2			upstream_gene_variant		ENST00000430524.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT2A	ENST00000252136.12	c.556C>T	p.Arg186Trp	missense_variant	2/12	1	NM_022727.6	P1
RANBP1	ENST00000430524.6			upstream_gene_variant		3	NM_001278639.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000722 AC: 11 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.0000294 AC: 7 AN: 238216 Hom.: 0 AF XY: 0.0000387 AC XY: 5 AN XY: 129136

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000930

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000140 AC: 20 AN: 1430574 Hom.: 0 Cov.: 32 AF XY: 0.0000142 AC XY: 10 AN XY: 706688

Gnomad4 AFR exome AF: 0.0000613

Gnomad4 AMR exome AF: 0.000166

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000825

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152376 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74510

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000522

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

Bravo AF: 0.000110

ExAC AF: 0.0000330 AC: 4

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

Feb 17, 2023

The c.556C>T (p.R186W) alteration is located in exon 2 (coding exon 2) of the TRMT2A gene. This alteration results from a C to T substitution at nucleotide position 556, causing the arginine (R) at amino acid position 186 to be replaced by a tryptophan (W). 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	0.099
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.072	T;T;.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.60	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.048	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.018	B;B;.;B
Vest4		0.32
MutPred		0.54		Gain of catalytic residue at L184 (P = 0.0021);Gain of catalytic residue at L184 (P = 0.0021);Gain of catalytic residue at L184 (P = 0.0021);Gain of catalytic residue at L184 (P = 0.0021);
MVP		0.085
MPC		0.12
ClinPred		0.055	T
GERP RS		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.63

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: rs201499233; hg19: chr22-20103604; COSMIC: COSV52813815; COSMIC: COSV52813815;