NM_144964.4:c.559T>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_144964.4(TRMT10B):c.559T>C(p.Phe187Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TRMT10B
NM_144964.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.69

Publications

0 publications found

Variant links:

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]

TRMT10B links:

ENSG00000255872 (HGNC:):

ENSG00000255872 links:

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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Illumina
pontocerebellar hypoplasia type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EXOSC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMT10B	NM_144964.4 link	c.559T>C	p.Phe187Leu	missense_variant	Exon 5 of 9	ENST00000297994.4	NP_659401.2	Q6PF06-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRMT10B	ENST00000297994.4 link	c.559T>C	p.Phe187Leu	missense_variant	Exon 5 of 9	1	NM_144964.4	ENSP00000297994.3		Q6PF06-1
ENSG00000255872	ENST00000540557.1 link	n.*910+15700A>G		intron_variant	Intron 9 of 11	5		ENSP00000457548.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248876

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.0000646

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:

6.85e-7

AC:

AN:

1460544

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726452

show subpopulations

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

African (AFR)

AF:

0.0000299

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111132

Other (OTH)

AF:

0.00

AC:

AN:

60328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 21, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.559T>C (p.F187L) alteration is located in exon 5 (coding exon 4) of the TRMT10B gene. This alteration results from a T to C substitution at nucleotide position 559, causing the phenylalanine (F) at amino acid position 187 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

Pathogenic

0.99

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

.;.;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.022

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.9

.;.;M

PhyloP100

6.7

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.2

D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.014

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

0.35, 0.067

.;B;B

Vest4

0.74

MutPred

0.62

.;.;Loss of loop (P = 0.0512);

MVP

0.29

MPC

0.067

ClinPred

0.97

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.60

Mutation Taster

=46/54

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_144964.4:c.559T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over