X-101022037-A-G

Variant names:

• chrX-101022037-A-G
• rs1388842875
• NM_024917.6:c.782T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_024917.6(TRMT2B):​c.782T>C​(p.Ile261Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,389 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: TRMT2B NM_024917.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0920
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034579486).
• BP6: Variant X-101022037-A-G is Benign according to our data. Variant chrX-101022037-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2617776.Status of the report is criteria_provided_single_submitter, 1 stars.

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.782T>C	p.Ile261Thr	missense	Exon 9 of 14	NP_079193.2
	TRMT2B	NM_001167970.2		c.782T>C	p.Ile261Thr	missense	Exon 9 of 14	NP_001161442.1	Q96GJ1-1
	TRMT2B	NM_001167972.2		c.782T>C	p.Ile261Thr	missense	Exon 8 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.782T>C	p.Ile261Thr	missense	Exon 9 of 14	ENSP00000362027.3	Q96GJ1-1
	TRMT2B	ENST00000372935.5	TSL:1	c.782T>C	p.Ile261Thr	missense	Exon 9 of 14	ENSP00000362026.1	Q96GJ1-1
	TRMT2B	ENST00000545398.5	TSL:1	c.782T>C	p.Ile261Thr	missense	Exon 8 of 13	ENSP00000438134.1	Q96GJ1-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096389 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361777

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26372

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30191

South Asian (SAS) AF: 0.00 AC: 0 AN: 54084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840473

Other (OTH) AF: 0.00 AC: 0 AN: 46038

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.052
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.5
DANN	Benign	0.49
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.092
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.038
Sift	Benign	0.53	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.52		Gain of disorder (P = 0.0339)
MVP		0.29
MPC		0.37
ClinPred		0.049	T
GERP RS		-0.97
Varity_R		0.038
gMVP		0.30
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1388842875; hg19: chrX-100277026;