X-101021223-C-A

Variant names:

• chrX-101021223-C-A
• rs145912589
• NM_024917.6:c.944G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_024917.6(TRMT2B):​c.944G>T​(p.Arg315Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,209,749 control chromosomes in the GnomAD database, including 1 homozygotes. There are 36 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R315C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., 24 hem., cov: 23)
  • Exomes 𝑓: 0.000057 (1 hom. 12 hem.)
• Consequence: TRMT2B NM_024917.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.375
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09814417).
• BS2: High Hemizygotes in GnomAd4 at 24 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024917.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT2B	NM_024917.6	MANE Select	c.944G>T	p.Arg315Leu	missense	Exon 10 of 14	NP_079193.2
	TRMT2B	NM_001167970.2		c.944G>T	p.Arg315Leu	missense	Exon 10 of 14	NP_001161442.1	Q96GJ1-1
	TRMT2B	NM_001167972.2		c.944G>T	p.Arg315Leu	missense	Exon 9 of 13	NP_001161444.1	Q96GJ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT2B	ENST00000372936.4	TSL:1 MANE Select	c.944G>T	p.Arg315Leu	missense	Exon 10 of 14	ENSP00000362027.3	Q96GJ1-1
	TRMT2B	ENST00000372935.5	TSL:1	c.944G>T	p.Arg315Leu	missense	Exon 10 of 14	ENSP00000362026.1	Q96GJ1-1
	TRMT2B	ENST00000545398.5	TSL:1	c.944G>T	p.Arg315Leu	missense	Exon 9 of 13	ENSP00000438134.1	Q96GJ1-1

Frequencies

GnomAD3 genomes AF: 0.000536 AC: 60 AN: 111860 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000877

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

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: 0.000669

GnomAD2 exomes AF: 0.0000928 AC: 17 AN: 183172 AF XY: 0.0000591

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000574 AC: 63 AN: 1097836 Hom.: 1 Cov.: 30 AF XY: 0.0000330 AC XY: 12 AN XY: 363192

African (AFR) AF: 0.00121 AC: 32 AN: 26392

American (AMR) AF: 0.000483 AC: 17 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841766

Other (OTH) AF: 0.000239 AC: 11 AN: 46078

GnomAD4 genome AF: 0.000536 AC: 60 AN: 111913 Hom.: 0 Cov.: 23 AF XY: 0.000704 AC XY: 24 AN XY: 34085

African (AFR) AF: 0.000875 AC: 27 AN: 30866

American (AMR) AF: 0.00306 AC: 32 AN: 10451

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2689

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6065

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53231

Other (OTH) AF: 0.000661 AC: 1 AN: 1514

Alfa AF: 0.000160 Hom.: 9

Bravo AF: 0.00114

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.38
PrimateAI	Benign	0.18	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.61	P
Vest4		0.26
MVP		0.33
MPC		1.1
ClinPred		0.43	T
GERP RS		1.1
Varity_R		0.72
gMVP		0.89
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145912589; hg19: chrX-100276212;