rs875989831

Positions:

• chr3-101565595-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The ENST00000309922.7(TRMT10C):​c.814A>G​(p.Thr272Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T272S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRMT10C ENST00000309922.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.10

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-101565595-A-T is described in Lovd as [Pathogenic].
• PP5: Variant 3-101565595-A-G is Pathogenic according to our data. Variant chr3-101565595-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 224317.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT10C	NM_017819.4	c.814A>G	p.Thr272Ala	missense_variant	2/2	ENST00000309922.7	NP_060289.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT10C	ENST00000309922.7	c.814A>G	p.Thr272Ala	missense_variant	2/2	1	NM_017819.4	ENSP00000312356	P1
TRMT10C	ENST00000495642.1	c.814A>G	p.Thr272Ala	missense_variant	2/2	3		ENSP00000419389

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461814 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727204

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Mar 08, 2016

- -

Combined oxidative phosphorylation defect type 30 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.036	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.54		Loss of methylation at K268 (P = 0.085);Loss of methylation at K268 (P = 0.085);
MVP		0.41
MPC		0.66
ClinPred		0.97	D
GERP RS		6.2
Varity_R		0.90
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs875989831; hg19: chr3-101284439;