rs11254413

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004412.7(TRDMT1):​c.301C>T​(p.His101Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,604,150 control chromosomes in the GnomAD database, including 160,429 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (14372 hom., cov: 27)
  • Exomes 𝑓: 0.44 (146057 hom.)
• Consequence: TRDMT1 NM_004412.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.553

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.259778E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDMT1	NM_004412.7	c.301C>T	p.His101Tyr	missense_variant	Exon 4 of 11	ENST00000377799.8	NP_004403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDMT1	ENST00000377799.8	c.301C>T	p.His101Tyr	missense_variant	Exon 4 of 11	1	NM_004412.7	ENSP00000367030.3

Frequencies

GnomAD3 genomes AF: 0.435 AC: 65189 AN: 149850 Hom.: 14355 Cov.: 27

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.458

GnomAD3 exomes AF: 0.410 AC: 101539 AN: 247550 Hom.: 21652 AF XY: 0.413 AC XY: 55383 AN XY: 133958

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.239

Gnomad SAS exome AF: 0.344

Gnomad FIN exome AF: 0.431

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.445 AC: 646854 AN: 1454184 Hom.: 146057 Cov.: 33 AF XY: 0.443 AC XY: 320318 AN XY: 723496

Gnomad4 AFR exome AF: 0.421

Gnomad4 AMR exome AF: 0.362

Gnomad4 ASJ exome AF: 0.394

Gnomad4 EAS exome AF: 0.227

Gnomad4 SAS exome AF: 0.355

Gnomad4 FIN exome AF: 0.433

Gnomad4 NFE exome AF: 0.466

Gnomad4 OTH exome AF: 0.436

GnomAD4 genome AF: 0.435 AC: 65223 AN: 149966 Hom.: 14372 Cov.: 27 AF XY: 0.429 AC XY: 31361 AN XY: 73152

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.413

Gnomad4 EAS AF: 0.249

Gnomad4 SAS AF: 0.360

Gnomad4 FIN AF: 0.428

Gnomad4 NFE AF: 0.465

Gnomad4 OTH AF: 0.461

Alfa AF: 0.455 Hom.: 40551

Bravo AF: 0.433

TwinsUK AF: 0.457 AC: 1694

ALSPAC AF: 0.462 AC: 1779

ESP6500AA AF: 0.431 AC: 1898

ESP6500EA AF: 0.453 AC: 3897

ExAC AF: 0.417 AC: 50690

Asia WGS AF: 0.346 AC: 1205 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.39
DANN	Benign	0.20
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.00033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.22	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.083
Sift	Benign	0.76	T
Sift4G	Benign	0.44	T
Polyphen		0.011	B
Vest4		0.17
MPC		0.017
ClinPred		0.0022	T
GERP RS		-2.1
Varity_R		0.27
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11254413; hg19: chr10-17204187; COSMIC: COSV58318669;