X-101020588-C-T

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

8
8
1
Splicing: ADA: 0.03469
2

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]

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
TRMT2BNM_024917.6 linkc.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 Appris UniProt
TRMT2BENST00000372936.4 linkc.1067G>A p.Gly356Asp missense_variant, splice_region_variant Exon 11 of 14 1 NM_024917.6 ENSP00000362027.3 Q96GJ1-1
TRMT2BENST00000372935.5 linkc.1067G>A p.Gly356Asp missense_variant, splice_region_variant Exon 11 of 14 1 ENSP00000362026.1 Q96GJ1-1
TRMT2BENST00000545398.5 linkc.1067G>A p.Gly356Asp missense_variant, splice_region_variant Exon 10 of 13 1 ENSP00000438134.1 Q96GJ1-1
TRMT2BENST00000372939.5 linkc.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:
1
AN:
111983
Hom.:
0
Cov.:
23
AF XY:
0.0000292
AC XY:
1
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:
2
AN:
1071968
Hom.:
0
Cov.:
26
AF XY:
0.00
AC XY:
0
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:
1
AN:
111983
Hom.:
0
Cov.:
23
AF XY:
0.0000292
AC XY:
1
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
D
BayesDel_noAF
Pathogenic
0.39
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D;.;D;D
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.95
D;D;.;.
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Uncertain
0.42
D
MutationAssessor
Pathogenic
5.0
H;.;H;H
PrimateAI
Uncertain
0.53
T
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
D
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.

Other links and lift over

dbSNP: rs1167242652; hg19: chrX-100275577; API