Genetic Variant TRMT2B:p.Arg288Cys (chrX-101021305-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_024917.6(TRMT2B):c.862C>T(p.Arg288Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,092,903 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 3 hem. )

Consequence

TRMT2B
NM_024917.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1618917).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMT2B	NM_024917.6 link	c.862C>T	p.Arg288Cys	missense_variant	Exon 10 of 14	ENST00000372936.4	NP_079193.2	Q96GJ1-1A0A024RCF5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRMT2B	ENST00000372936.4 link	c.862C>T	p.Arg288Cys	missense_variant	Exon 10 of 14	1	NM_024917.6	ENSP00000362027.3	Q96GJ1-1
TRMT2B	ENST00000372935.5 link	c.862C>T	p.Arg288Cys	missense_variant	Exon 10 of 14	1		ENSP00000362026.1	Q96GJ1-1
TRMT2B	ENST00000545398.5 link	c.862C>T	p.Arg288Cys	missense_variant	Exon 9 of 13	1		ENSP00000438134.1	Q96GJ1-1
TRMT2B	ENST00000372939.5 link	c.727C>T	p.Arg243Cys	missense_variant	Exon 10 of 14	1		ENSP00000362030.1	Q96GJ1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000168

AC:

AN:

178494

Hom.:

AF XY:

0.0000157

AC XY:

AN XY:

63634

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000369

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000555

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.00000457

AC:

AN:

1092903

Hom.:

Cov.:

AF XY:

0.00000836

AC XY:

AN XY:

358693

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000287

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000187

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.862C>T (p.R288C) alteration is located in exon 10 (coding exon 8) of the TRMT2B gene. This alteration results from a C to T substitution at nucleotide position 862, causing the arginine (R) at amino acid position 288 to be replaced by a cysteine (C). 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

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.;T;T

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.90

D;D;.;.

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.9

L;.;L;L

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-5.6

D;D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

0.068

B;D;B;B

Vest4

0.074

MVP

0.51

MPC

0.50

ClinPred

0.42

GERP RS

1.9

Varity_R

0.20

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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