Genetic Variant TRMT2B:p.Gly356Asp (chrX-101020588-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024917.6(TRMT2B):c.1067G>A(p.Gly356Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,183,951 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000019 ( 0 hom. 0 hem. )

Consequence

TRMT2B
NM_024917.6 missense, splice_region

Scores

Splicing: ADA: 0.03469

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMT2B	NM_024917.6 link	c.1067G>A	p.Gly356Asp	missense_variant, splice_region_variant	Exon 11 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.1067G>A	p.Gly356Asp	missense_variant, splice_region_variant	Exon 11 of 14	1	NM_024917.6	ENSP00000362027.3	Q96GJ1-1
TRMT2B	ENST00000372935.5 link	c.1067G>A	p.Gly356Asp	missense_variant, splice_region_variant	Exon 11 of 14	1		ENSP00000362026.1	Q96GJ1-1
TRMT2B	ENST00000545398.5 link	c.1067G>A	p.Gly356Asp	missense_variant, splice_region_variant	Exon 10 of 13	1		ENSP00000438134.1	Q96GJ1-1
TRMT2B	ENST00000372939.5 link	c.932G>A	p.Gly311Asp	missense_variant, splice_region_variant	Exon 11 of 14	1		ENSP00000362030.1	Q96GJ1-3

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111983

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34205

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000187

AC:

AN:

1071968

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

338754

show subpopulations

Gnomad4 AFR exome

AF:

0.0000771

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

AF:

0.00000893

AC:

AN:

111983

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34205

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1067G>A (p.G356D) alteration is located in exon 11 (coding exon 9) of the TRMT2B gene. This alteration results from a G to A substitution at nucleotide position 1067, causing the glycine (G) at amino acid position 356 to be replaced by an aspartic acid (D). 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

0.72

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;D;D

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

D;D;.;.

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

5.0

H;.;H;H

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-6.6

D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.93

MutPred

0.89

Loss of catalytic residue at G354 (P = 0.0567);.;Loss of catalytic residue at G354 (P = 0.0567);Loss of catalytic residue at G354 (P = 0.0567);

MVP

0.70

MPC

1.1

ClinPred

1.0

GERP RS

3.7

Varity_R

0.85

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.035

dbscSNV1_RF

Benign

0.29

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