4-99549209-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001134665.3(TRMT10A):c.899G>A(p.Gly300Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G300R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: TRMT10A NM_001134665.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.296

Genes affected

TRMT10A (HGNC:28403): (tRNA methyltransferase 10A) This gene encodes a protein that belongs to the tRNA (Guanine-1)-methyltransferase family. A similar gene in yeast modifies several different tRNA species. Mutations in this gene are associated with microcephaly, short stature, and impaired glucose metabolism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0202142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT10A	NM_001134665.3	c.899G>A	p.Gly300Asp	missense_variant	8/8	ENST00000394876.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT10A	ENST00000394876.7	c.899G>A	p.Gly300Asp	missense_variant	8/8	1	NM_001134665.3	P1
TRMT10A	ENST00000273962.7	c.899G>A	p.Gly300Asp	missense_variant	8/8	1		P1
TRMT10A	ENST00000394877.7	c.899G>A	p.Gly300Asp	missense_variant	8/8	2		P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251356 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135844

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 300 of the TRMT10A protein (p.Gly300Asp). This variant is present in population databases (rs771561899, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TRMT10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1441812). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.59
Dann	Benign	0.29
DEOGEN2	Benign	0.0035	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0020	N
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.73	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.041
MutPred		0.15		Gain of glycosylation at S302 (P = 0.0054);Gain of glycosylation at S302 (P = 0.0054);Gain of glycosylation at S302 (P = 0.0054);
MVP		0.040
MPC		0.19
ClinPred		0.017	T
GERP RS		-3.0
Varity_R		0.081
gMVP		0.066

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

LitVar

Other links and lift over

dbSNP: rs771561899; hg19: chr4-100470366;