9-37776285-G-T

Variant names:

• chr9-37776285-G-T
• rs781416388
• NM_144964.4:c.724G>T

Variant summary

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

The NM_144964.4(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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRMT10B NM_144964.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57
• Publications: 0 publications found

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]

EXOSC3 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144964.4. 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
	TRMT10B	NM_144964.4	MANE Select	c.724G>T	p.Val242Leu	missense	Exon 8 of 9	NP_659401.2	Q6PF06-1
	TRMT10B	NM_001286950.2		c.571G>T	p.Val191Leu	missense	Exon 7 of 8	NP_001273879.1	Q6PF06-5
	TRMT10B	NM_001286952.2		c.490G>T	p.Val164Leu	missense	Exon 6 of 7	NP_001273881.1	Q6PF06-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT10B	ENST00000297994.4	TSL:1 MANE Select	c.724G>T	p.Val242Leu	missense	Exon 8 of 9	ENSP00000297994.3	Q6PF06-1
	TRMT10B	ENST00000488673.6	TSL:1	n.*311G>T		non_coding_transcript_exon	Exon 8 of 9	ENSP00000437395.1	Q6PF06-3
	TRMT10B	ENST00000488673.6	TSL:1	n.*311G>T		3_prime_UTR	Exon 8 of 9	ENSP00000437395.1	Q6PF06-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 171926 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 29710

American (AMR) AF: 0.00 AC: 0 AN: 30066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23570

East Asian (EAS) AF: 0.00 AC: 0 AN: 36032

South Asian (SAS) AF: 0.00 AC: 0 AN: 73118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078454

Other (OTH) AF: 0.00 AC: 0 AN: 56988

GnomAD4 genome Cov.: 32

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	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
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N
PhyloP100		2.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.044
Sift	Benign	0.89	T
Sift4G	Benign	1.0	T
Polyphen		0.0	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
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs781416388; hg19: chr9-37776282;