10-17157457-C-A

Variant names:

• chr10-17157457-C-A
• rs746221561
• NM_004412.7:c.871G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004412.7(TRDMT1):​c.871G>T​(p.Val291Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. V291M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRDMT1 NM_004412.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18435562).

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.871G>T	p.Val291Leu	missense	Exon 8 of 11	NP_004403.1	O14717-1
	TRDMT1	NM_001351220.2		c.871G>T	p.Val291Leu	missense	Exon 8 of 11	NP_001338149.1
	TRDMT1	NM_001321007.2		c.658G>T	p.Val220Leu	missense	Exon 9 of 12	NP_001307936.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDMT1	ENST00000377799.8	TSL:1 MANE Select	c.871G>T	p.Val291Leu	missense	Exon 8 of 11	ENSP00000367030.3	O14717-1
	TRDMT1	ENST00000354631.7	TSL:1	n.*891G>T		non_coding_transcript_exon	Exon 9 of 12	ENSP00000346652.3	Q7Z3E4
	TRDMT1	ENST00000354631.7	TSL:1	n.*891G>T		3_prime_UTR	Exon 9 of 12	ENSP00000346652.3	Q7Z3E4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248486 AF XY: 0.00000744

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454528 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 722062

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106190

Other (OTH) AF: 0.00 AC: 0 AN: 60096

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.86
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.3
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.085
Sift	Benign	0.21	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.57		Loss of catalytic residue at V291 (P = 0.0879)
MVP		0.34
MPC		0.016
ClinPred		0.034	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.52
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs746221561; hg19: chr10-17199456;