10-17149110-C-A

Variant names:

• chr10-17149110-C-A
• rs200539562
• NM_004412.7:c.1106G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004412.7(TRDMT1):​c.1106G>T​(p.Arg369Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,036 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R369H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRDMT1 NM_004412.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• Publications: 2 publications found

Genes affected

TRDMT1 (HGNC:2977): (tRNA aspartic acid methyltransferase 1) This gene encodes a protein responsible for the methylation of aspartic acid transfer RNA, specifically at the cytosine-38 residue in the anticodon loop. This enzyme also possesses residual DNA-(cytosine-C5) methyltransferase activity. While similar in sequence and structure to DNA cytosine methyltransferases, this gene is distinct and highly conserved in its function among taxa. [provided by RefSeq, Jun 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004412.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDMT1	NM_004412.7	MANE Select	c.1106G>T	p.Arg369Leu	missense	Exon 11 of 11	NP_004403.1	O14717-1
	TRDMT1	NM_001351219.2		c.1085G>T	p.Arg362Leu	missense	Exon 11 of 11	NP_001338148.1
	TRDMT1	NM_001351221.2		c.947G>T	p.Arg316Leu	missense	Exon 9 of 9	NP_001338150.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDMT1	ENST00000377799.8	TSL:1 MANE Select	c.1106G>T	p.Arg369Leu	missense	Exon 11 of 11	ENSP00000367030.3	O14717-1
	TRDMT1	ENST00000354631.7	TSL:1	n.*1126G>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000346652.3	Q7Z3E4
	TRDMT1	ENST00000354631.7	TSL:1	n.*1126G>T		3_prime_UTR	Exon 12 of 12	ENSP00000346652.3	Q7Z3E4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459036 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725874

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5144

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110964

Other (OTH) AF: 0.00 AC: 0 AN: 60216

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.12
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.6
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.098
Sift	Uncertain	0.023	D
Sift4G	Benign	0.12	T
Polyphen		0.40	B
Vest4		0.42
MutPred		0.68		Loss of methylation at R369 (P = 0.0312)
MVP		0.68
MPC		0.045
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.39
gMVP		0.54
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs200539562; hg19: chr10-17191109;