Genetic Variant TRMT2B:p.Ile144Thr (chrX-101037924-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024917.6(TRMT2B):c.431T>C(p.Ile144Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,097,062 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

TRMT2B
NM_024917.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.61

Variant links:

Genes affected

TRMT2B (HGNC:25748): (tRNA methyltransferase 2 homolog B) This gene encodes a homolog of the TRM2 gene in S. cerevisiae. The yeast gene encodes a tRNA methyltransferase that plays a role in tRNA maturation. The yeast protein also has endo-exonuclease activity and may be involved in DNA double strand break repair. Alternative splicing results in multiple transcripts encoding different isoforms. [provided by RefSeq, Nov 2009]

TRMT2B links:

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ACMG classification

Classification made for transcript

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=0.19822708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMT2B	NM_024917.6 link	c.431T>C	p.Ile144Thr	missense_variant	Exon 5 of 14	ENST00000372936.4	NP_079193.2	Q96GJ1-1A0A024RCF5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRMT2B	ENST00000372936.4 link	c.431T>C	p.Ile144Thr	missense_variant	Exon 5 of 14	1	NM_024917.6	ENSP00000362027.3		Q96GJ1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183017

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67465

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000526

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1097062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362456

show subpopulations

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:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.431T>C (p.I144T) alteration is located in exon 5 (coding exon 3) of the TRMT2B gene. This alteration results from a T to C substitution at nucleotide position 431, causing the isoleucine (I) at amino acid position 144 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

0.28

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.047

T;T;T

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.82

T;.;.

M_CAP

Benign

0.018

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.1

M;M;M

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.77

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.25

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

0.21

B;B;B

Vest4

0.38

MutPred

0.52

Gain of glycosylation at I144 (P = 0.0275);Gain of glycosylation at I144 (P = 0.0275);Gain of glycosylation at I144 (P = 0.0275);

MVP

0.76

MPC

0.58

ClinPred

0.23

GERP RS

3.2

Varity_R

0.13

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over