10-17162188-G-C

Variant names:

• chr10-17162188-G-C
• rs11254413
• NM_004412.7:c.301C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004412.7(TRDMT1):​c.301C>G​(p.His101Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRDMT1 NM_004412.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.553
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

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.301C>G	p.His101Asp	missense	Exon 4 of 11	NP_004403.1	O14717-1
	TRDMT1	NM_001351219.2		c.301C>G	p.His101Asp	missense	Exon 4 of 11	NP_001338148.1
	TRDMT1	NM_001351220.2		c.301C>G	p.His101Asp	missense	Exon 4 of 11	NP_001338149.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDMT1	ENST00000377799.8	TSL:1 MANE Select	c.301C>G	p.His101Asp	missense	Exon 4 of 11	ENSP00000367030.3	O14717-1
	TRDMT1	ENST00000436968.6	TSL:1	c.109-1814C>G		intron	N/A	ENSP00000390611.2	H0Y4A2
	TRDMT1	ENST00000354631.7	TSL:1	n.*321C>G		non_coding_transcript_exon	Exon 5 of 12	ENSP00000346652.3	Q7Z3E4

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457086 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724936

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33110

American (AMR) AF: 0.00 AC: 0 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.00 AC: 0 AN: 85680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109182

Other (OTH) AF: 0.0000166 AC: 1 AN: 60196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.55
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.87	P
Vest4		0.46
MutPred		0.56		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.65
MPC		0.073
ClinPred		0.61	D
GERP RS		-2.1
Varity_R		0.72
gMVP		0.88
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs11254413; hg19: chr10-17204187;