Genetic Variant TRMT10C:p.Arg181Leu (chr3-101565323-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_017819.4(TRMT10C):c.542G>T(p.Arg181Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000121 in 1,613,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TRMT10C
NM_017819.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 4.31

Publications

9 publications found

Variant links:

Genes affected

TRMT10C (HGNC:26022): (tRNA methyltransferase 10C, mitochondrial RNase P subunit) This gene encodes the precursor of a subunit of the mitochondrial ribonuclease P, which is involved in 5' processing of mitochondrial tRNAs. The encoded protein may confer RNA-binding capacity to mitochondrial ribonuclease P and may be essential for transcript processing, RNA modification, translation and mitochondrial respiration. [provided by RefSeq, Nov 2012]

TRMT10C Gene-Disease associations (from GenCC):

combined oxidative phosphorylation defect type 30
Inheritance: AR, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

TRMT10C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 3-101565323-G-T is Pathogenic according to our data. Variant chr3-101565323-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224316.

BP4

Computational evidence support a benign effect (MetaRNN=0.1815046). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017819.4. 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
	TRMT10C	NM_017819.4	MANE Select	c.542G>T	p.Arg181Leu	missense	Exon 2 of 2	NP_060289.2	Q7L0Y3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT10C	ENST00000309922.7	TSL:1 MANE Select	c.542G>T	p.Arg181Leu	missense	Exon 2 of 2	ENSP00000312356.6	Q7L0Y3
	TRMT10C	ENST00000495642.1	TSL:3	c.542G>T	p.Arg181Leu	missense	Exon 2 of 2	ENSP00000419389.1	C9JVB6

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000113

AC:

AN:

248734

AF XY:

0.000141

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000351

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000120

AC:

176

AN:

1461190

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

726874

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.000292

AC:

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000813

AC:

AN:

86096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000136

AC:

151

AN:

1111792

Other (OTH)

AF:

0.0000663

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.000524

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68026

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000828

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined oxidative phosphorylation defect type 30 (2)

not provided (2)

Mitochondrial disease (1)

not specified (1)

See cases (1)

TRMT10C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.78

M_CAP

Benign

0.0078

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.0

PhyloP100

4.3

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-4.4

REVEL

Benign

0.14

Sift

Uncertain

0.025

Sift4G

Benign

0.51

Polyphen

0.89

Vest4

0.80

MVP

0.39

MPC

0.55

ClinPred

0.26

GERP RS

4.8

Varity_R

0.27

gMVP

0.49

Mutation Taster

=24/76

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over