4-99558191-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134665.3(TRMT10A):c.206G>A(p.Arg69His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,596,038 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: TRMT10A NM_001134665.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.94

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00686568).
• BP6: Variant 4-99558191-C-T is Benign according to our data. Variant chr4-99558191-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 437058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00264 (401/152114) while in subpopulation NFE AF= 0.00348 (236/67896). AF 95% confidence interval is 0.00311. There are 5 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT10A	NM_001134665.3	c.206G>A	p.Arg69His	missense_variant	3/8	ENST00000394876.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT10A	ENST00000394876.7	c.206G>A	p.Arg69His	missense_variant	3/8	1	NM_001134665.3	P1

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 400 AN: 151996 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00257 AC: 600 AN: 233286 Hom.: 2 AF XY: 0.00268 AC XY: 337 AN XY: 125934

Gnomad AFR exome AF: 0.000379

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000192

Gnomad FIN exome AF: 0.00974

Gnomad NFE exome AF: 0.00316

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00244 AC: 3523 AN: 1443924 Hom.: 6 Cov.: 30 AF XY: 0.00243 AC XY: 1745 AN XY: 717820

Gnomad4 AFR exome AF: 0.000375

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00182

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000390

Gnomad4 FIN exome AF: 0.00866

Gnomad4 NFE exome AF: 0.00253

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00264 AC: 401 AN: 152114 Hom.: 5 Cov.: 33 AF XY: 0.00307 AC XY: 228 AN XY: 74368

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.00348

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00273 Hom.: 2

Bravo AF: 0.00153

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00266 AC: 323

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TRMT10A: BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 03, 2017

- -

TRMT10A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.090	T;T;T;T;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0069	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Benign	0.19
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.064	T;T;T;.;.
Polyphen		0.080	B;B;B;.;.
Vest4		0.34
MVP		0.60
MPC		0.19
ClinPred		0.034	T
GERP RS		5.8
Varity_R		0.33
gMVP		0.10

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: rs147815779; hg19: chr4-100479348; COSMIC: COSV104565001; COSMIC: COSV104565001;