X-101020552-C-T

Variant names:

• chrX-101020552-C-T
• rs1249351585
• NM_024917.6:c.1103G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_024917.6(TRMT2B):​c.1103G>A​(p.Arg368Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000579 in 1,209,350 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: TRMT2B NM_024917.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.40

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.063755095).
• BP6: Variant X-101020552-C-T is Benign according to our data. Variant chrX-101020552-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3461881.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMT2B	NM_024917.6	c.1103G>A	p.Arg368Gln	missense_variant	Exon 11 of 14	ENST00000372936.4	NP_079193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRMT2B	ENST00000372936.4	c.1103G>A	p.Arg368Gln	missense_variant	Exon 11 of 14	1	NM_024917.6	ENSP00000362027.3
TRMT2B	ENST00000372935.5	c.1103G>A	p.Arg368Gln	missense_variant	Exon 11 of 14	1		ENSP00000362026.1
TRMT2B	ENST00000545398.5	c.1103G>A	p.Arg368Gln	missense_variant	Exon 10 of 13	1		ENSP00000438134.1
TRMT2B	ENST00000372939.5	c.968G>A	p.Arg323Gln	missense_variant	Exon 11 of 14	1		ENSP00000362030.1

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 112122 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34292

Gnomad AFR AF: 0.000129

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: 0.00000273 AC: 3 AN: 1097228 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362602

Gnomad4 AFR exome AF: 0.0000379

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 112122 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34292

Gnomad4 AFR AF: 0.000129

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: 0.0000189

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 27, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	6.0
DANN	Benign	0.26
DEOGEN2	Benign	0.054	T;.;T;T
FATHMM_MKL	Benign	0.00083	N
LIST_S2	Benign	0.62	T;T;.;.
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.064	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.41	N;.;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.83	N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.90	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.075
MutPred		0.54		Loss of methylation at R368 (P = 0.176);.;Loss of methylation at R368 (P = 0.176);Loss of methylation at R368 (P = 0.176);
MVP		0.35
MPC		0.34
ClinPred		0.019	T
GERP RS		0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.16

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

Other links and lift over

dbSNP: rs1249351585; hg19: chrX-100275541;