Genetic Variant TRMT61A:p.Thr269Arg (chr14-103534757-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152307.3(TRMT61A):c.806C>G(p.Thr269Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. T269M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TRMT61A
NM_152307.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.95

Publications

0 publications found

Variant links:

Genes affected

TRMT61A (HGNC:23790): (tRNA methyltransferase 61A) Enables mRNA (adenine-N1-)-methyltransferase activity. Involved in mRNA methylation. Predicted to be located in nucleoplasm. Predicted to be part of tRNA (m1A) methyltransferase complex. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TRMT61A links:

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ACMG classification

Classification was made for transcript

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=0.0942938).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152307.3. 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
	TRMT61A	NM_152307.3	MANE Select	c.806C>G	p.Thr269Arg	missense	Exon 4 of 4	NP_689520.2	Q96FX7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRMT61A	ENST00000389749.9	TSL:1 MANE Select	c.806C>G	p.Thr269Arg	missense	Exon 4 of 4	ENSP00000374399.4	Q96FX7
TRMT61A	ENST00000299202.4	TSL:1	c.509C>G	p.Thr170Arg	missense	Exon 3 of 3	ENSP00000299202.4	H0Y2Q1
TRMT61A	ENST00000896880.1		c.806C>G	p.Thr269Arg	missense	Exon 3 of 3	ENSP00000566939.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1436012

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712938

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33142

American (AMR)

AF:

0.00

AC:

AN:

42560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25614

East Asian (EAS)

AF:

0.00

AC:

AN:

38878

South Asian (SAS)

AF:

0.00

AC:

AN:

84000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43696

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102902

Other (OTH)

AF:

0.00

AC:

AN:

59486

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.055

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.69

M_CAP

Benign

0.027

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.085

PhyloP100

1.9

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.84

REVEL

Benign

0.049

Sift

Benign

0.63

Sift4G

Benign

0.56

Polyphen

0.43

Vest4

0.14

MutPred

0.38

Gain of catalytic residue at R266 (P = 0.0021)

MVP

0.20

MPC

0.58

ClinPred

0.25

GERP RS

2.3

Varity_R

0.21

gMVP

0.72

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over