Variant 19-13104975-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001136035.4(TRMT1):c.1940C>T(p.Pro647Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 0.0000021 ( 0 hom. )

Consequence

TRMT1
NM_001136035.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.935

Variant links:

Genes affected

TRMT1 (HGNC:25980): (tRNA methyltransferase 1) This gene encodes a tRNA-modifying enzyme that acts as a dimethyltransferase, modifying a single guanine residue at position 26 of the tRNA. The encoded enzyme has both mono- and dimethylase activity when exogenously expressed, and uses S-adenosyl methionine as a methyl donor. The C-terminal region of the encoded protein has both a zinc finger motif, and an arginine/proline-rich region. Mutations in this gene have been implicated in autosomal recessive intellectual disorder (ARID). Alternative splicing results in multiple transcript variants encoding different isoforms. There is a pseudogene of this gene on the X chromosome. [provided by RefSeq, May 2017]

TRMT1 links:

TRMT1 (HGNC:):

TRMT1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11494437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT1	NM_001136035.4 linkuse as main transcript	c.1940C>T	p.Pro647Leu	missense_variant	17/17	ENST00000357720.9	NP_001129507.1	Q9NXH9-1A0A024R7I5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT1	ENST00000357720.9 linkuse as main transcript	c.1940C>T	p.Pro647Leu	missense_variant	17/17	2	NM_001136035.4	ENSP00000350352.4		Q9NXH9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250868

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135574

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727068

show subpopulations

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:

0.0000188

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.1940C>T (p.P647L) alteration is located in exon 16 (coding exon 16) of the TRMT1 gene. This alteration results from a C to T substitution at nucleotide position 1940, causing the proline (P) at amino acid position 647 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

0.064

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.036

T;T;.;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.70

T;.;T;.

M_CAP

Benign

0.015

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.81

L;L;.;L

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.5

N;N;N;.

REVEL

Benign

0.071

Sift

Uncertain

0.0080

D;D;D;.

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

0.14

B;B;B;B

Vest4

0.29

MutPred

0.16

Loss of glycosylation at P647 (P = 0.0326);Loss of glycosylation at P647 (P = 0.0326);.;Loss of glycosylation at P647 (P = 0.0326);

MVP

0.46

MPC

0.14

ClinPred

0.16

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over