22-20116113-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022727.6(TRMT2A):c.524T>C(p.Leu175Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRMT2A NM_022727.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.65

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT2A	NM_022727.6	c.524T>C	p.Leu175Pro	missense_variant	2/12	ENST00000252136.12
RANBP1	NM_001278639.2	c.-72A>G		5_prime_UTR_variant	1/6	ENST00000430524.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT2A	ENST00000252136.12	c.524T>C	p.Leu175Pro	missense_variant	2/12	1	NM_022727.6	P1
RANBP1	ENST00000430524.6	c.-72A>G		5_prime_UTR_variant	1/6	3	NM_001278639.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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 06, 2022

The c.524T>C (p.L175P) alteration is located in exon 2 (coding exon 2) of the TRMT2A gene. This alteration results from a T to C substitution at nucleotide position 524, causing the leucine (L) at amino acid position 175 to be replaced by a proline (P). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.5	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.1	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.96
MutPred		0.71		Gain of catalytic residue at P174 (P = 0.015);Gain of catalytic residue at P174 (P = 0.015);Gain of catalytic residue at P174 (P = 0.015);Gain of catalytic residue at P174 (P = 0.015);
MVP		0.65
MPC		0.26
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.95

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: rs2050007688; hg19: chr22-20103636;