19-13105364-C-G

Position:

• chr19-13105364-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001136035.4(TRMT1):​c.1736G>C​(p.Arg579Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRMT1 NM_001136035.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.316

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35808408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT1	NM_001136035.4	c.1736G>C	p.Arg579Thr	missense_variant	16/17	ENST00000357720.9	NP_001129507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT1	ENST00000357720.9	c.1736G>C	p.Arg579Thr	missense_variant	16/17	2	NM_001136035.4	ENSP00000350352.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2024

The c.1736G>C (p.R579T) alteration is located in exon 15 (coding exon 15) of the TRMT1 gene. This alteration results from a G to C substitution at nucleotide position 1736, causing the arginine (R) at amino acid position 579 to be replaced by a threonine (T). 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	0.24
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.80
DEOGEN2	Benign	0.087	T;T;.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.82	T;.;T;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	M;M;.;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.4	N;N;N;.
REVEL	Benign	0.026
Sift	Benign	0.041	D;D;D;.
Sift4G	Uncertain	0.037	D;D;D;D
Polyphen		0.26	B;B;B;B
Vest4		0.54
MutPred		0.39		Gain of phosphorylation at R579 (P = 0.0128);Gain of phosphorylation at R579 (P = 0.0128);.;Gain of phosphorylation at R579 (P = 0.0128);
MVP		0.46
MPC		0.27
ClinPred		0.58	D
GERP RS		0.64
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Varity_R		0.079
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13216178;