1-100133173-C-A

Position:

• chr1-100133173-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_019083.3(TRMT13):​c.5C>A​(p.Ala2Glu) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRMT13 NM_019083.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.783

Genes affected

TRMT13 (HGNC:25502): (tRNA methyltransferase 13 homolog) Predicted to enable tRNA methyltransferase activity. Predicted to be involved in tRNA methylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity TRM13_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14281961).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT13	NM_019083.3	c.5C>A	p.Ala2Glu	missense_variant	1/11	ENST00000370141.8	NP_061956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT13	ENST00000370141.8	c.5C>A	p.Ala2Glu	missense_variant	1/11	1	NM_019083.3	ENSP00000359160	P1
TRMT13	ENST00000370143.5	c.5C>A	p.Ala2Glu	missense_variant	1/5	3		ENSP00000359162
TRMT13	ENST00000482437.5	c.5C>A	p.Ala2Glu	missense_variant, NMD_transcript_variant	1/8	2		ENSP00000432616
TRMT13	ENST00000370139.1			upstream_gene_variant		3		ENSP00000359158

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The c.5C>A (p.A2E) alteration is located in exon 1 (coding exon 1) of the TRMT13 gene. This alteration results from a C to A substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 to be replaced by a glutamic acid (E). 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	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	.;L
MutationTaster	Benign	0.87	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.17	N;N
REVEL	Benign	0.053
Sift	Benign	0.079	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0070	.;B
Vest4		0.28
MutPred		0.18		Gain of solvent accessibility (P = 0.08);Gain of solvent accessibility (P = 0.08);
MVP		0.41
MPC		0.21
ClinPred		0.82	D
GERP RS		1.7
Varity_R		0.076
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr1-100598729; COSMIC: COSV54930710; COSMIC: COSV54930710;