9-37776285-G-T

Position:

• chr9-37776285-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000297994.4(TRMT10B):​c.724G>T​(p.Val242Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,384,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. V242A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRMT10B ENST00000297994.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

Genes affected

TRMT10B (HGNC:26454): (tRNA methyltransferase 10B) Enables tRNA (guanine-N1-)-methyltransferase activity. Predicted to be involved in mitochondrial tRNA processing. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255872 (HGNC:):

EXOSC3 (HGNC:17944): (exosome component 3) This gene encodes a non-catalytic component of the human exosome, a complex with 3'-5' exoribonuclease activity that plays a role in numerous RNA processing and degradation activities. Related pseudogenes of this gene are found on chromosome 19 and 21. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055407435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT10B	NM_144964.4	c.724G>T	p.Val242Leu	missense_variant	8/9	ENST00000297994.4	NP_659401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT10B	ENST00000297994.4	c.724G>T	p.Val242Leu	missense_variant	8/9	1	NM_144964.4	ENSP00000297994.3
ENSG00000255872	ENST00000540557.1	n.*910+7629C>A		intron_variant		5		ENSP00000457548.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1384048 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 685460

Gnomad4 AFR exome AF: 0.00

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2024

The c.724G>T (p.V242L) alteration is located in exon 8 (coding exon 7) of the TRMT10B gene. This alteration results from a G to T substitution at nucleotide position 724, causing the valine (V) at amino acid position 242 to be replaced by a leucine (L). 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	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.0050	.;.;.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	.;.;.;N
MutationTaster	Benign	0.52	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.34	N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.89	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0, 0.0010	.;.;B;B
Vest4		0.098
MutPred		0.58		.;.;.;Loss of methylation at K241 (P = 0.0354);
MVP		0.12
MPC		0.046
ClinPred		0.49	T
GERP RS		4.4
Varity_R		0.12
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs781416388; hg19: chr9-37776282;