10-17149125-A-G

Position:

• chr10-17149125-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004412.7(TRDMT1):​c.1091T>C​(p.Ile364Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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: TRDMT1 NM_004412.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.20

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24430415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDMT1	NM_004412.7	c.1091T>C	p.Ile364Thr	missense_variant	11/11	ENST00000377799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDMT1	ENST00000377799.8	c.1091T>C	p.Ile364Thr	missense_variant	11/11	1	NM_004412.7	P1
TRDMT1	ENST00000354631.7	c.*1111T>C		3_prime_UTR_variant, NMD_transcript_variant	12/12	1
TRDMT1	ENST00000495022.5	c.*756T>C		3_prime_UTR_variant, NMD_transcript_variant	9/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Feb 28, 2023

The c.1091T>C (p.I364T) alteration is located in exon 11 (coding exon 11) of the TRDMT1 gene. This alteration results from a T to C substitution at nucleotide position 1091, causing the isoleucine (I) at amino acid position 364 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	0.099
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.78
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.23
Sift	Benign	0.66	T
Sift4G	Benign	0.56	T
Polyphen		0.0040	B
Vest4		0.069
MutPred		0.61		Gain of disorder (P = 0.0087);
MVP		0.75
MPC		0.023
ClinPred		0.37	T
GERP RS		3.2
Varity_R		0.15
gMVP		0.46

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: chr10-17191124;