19-13105063-C-T

Variant names:

• chr19-13105063-C-T
• rs767856855
• NM_001136035.4:c.1852G>A

Variant summary

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

The NM_001136035.4(TRMT1):​c.1852G>A​(p.Asp618Asn) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D618Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRMT1 NM_001136035.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29

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]

LOC105372282 (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=0.35586277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMT1	NM_001136035.4	c.1852G>A	p.Asp618Asn	missense_variant	Exon 17 of 17	ENST00000357720.9	NP_001129507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRMT1	ENST00000357720.9	c.1852G>A	p.Asp618Asn	missense_variant	Exon 17 of 17	2	NM_001136035.4	ENSP00000350352.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1442380 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 715490

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 02, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;T;.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T;.;T;.
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M;.;M
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.11	T;T;T;.
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.089	B;B;B;B
Vest4		0.24
MutPred		0.77		Gain of MoRF binding (P = 0.0519);Gain of MoRF binding (P = 0.0519);.;Gain of MoRF binding (P = 0.0519);
MVP		0.63
MPC		0.17
ClinPred		0.70	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs767856855; hg19: chr19-13215877;