Genetic Variant TRDMT1:p.His101Asn (chr10-17162188-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_004412.7(TRDMT1):c.301C>A(p.His101Asn) 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TRDMT1
NM_004412.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.553

Publications

0 publications found

Variant links:

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]

TRDMT1 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRDMT1	NM_004412.7	MANE Select	c.301C>A	p.His101Asn	missense	Exon 4 of 11	NP_004403.1	O14717-1
TRDMT1	NM_001351219.2		c.301C>A	p.His101Asn	missense	Exon 4 of 11	NP_001338148.1
TRDMT1	NM_001351220.2		c.301C>A	p.His101Asn	missense	Exon 4 of 11	NP_001338149.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRDMT1	ENST00000377799.8	TSL:1 MANE Select	c.301C>A	p.His101Asn	missense	Exon 4 of 11	ENSP00000367030.3	O14717-1
TRDMT1	ENST00000436968.6	TSL:1	c.109-1814C>A		intron	N/A	ENSP00000390611.2	H0Y4A2
TRDMT1	ENST00000354631.7	TSL:1	n.*321C>A		non_coding_transcript_exon	Exon 5 of 12	ENSP00000346652.3	Q7Z3E4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457086

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724936

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33110

American (AMR)

AF:

0.00

AC:

AN:

44366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39440

South Asian (SAS)

AF:

0.00

AC:

AN:

85680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1109182

Other (OTH)

AF:

0.00

AC:

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Pathogenic

0.82

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.0

PhyloP100

0.55

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-5.2

REVEL

Benign

0.16

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.016

Polyphen

0.29

Vest4

0.39

MutPred

0.45

Loss of stability (P = 0.111)

MVP

0.56

MPC

0.020

ClinPred

0.73

GERP RS

-2.1

Varity_R

0.74

gMVP

0.77

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over