rs143207059

chr4-99549153-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001134665.3(TRMT10A):c.955C>A(p.Pro319Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,613,968 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00079 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TRMT10A NM_001134665.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.522

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048806667).
• BP6: Variant 4-99549153-G-T is Benign according to our data. Variant chr4-99549153-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437054.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000789 (120/152152) while in subpopulation AFR AF= 0.00248 (103/41504). AF 95% confidence interval is 0.00209. There are 3 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT10A	NM_001134665.3	c.955C>A	p.Pro319Thr	missense_variant	8/8	ENST00000394876.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT10A	ENST00000394876.7	c.955C>A	p.Pro319Thr	missense_variant	8/8	1	NM_001134665.3	P1
TRMT10A	ENST00000273962.7	c.955C>A	p.Pro319Thr	missense_variant	8/8	1		P1
TRMT10A	ENST00000394877.7	c.955C>A	p.Pro319Thr	missense_variant	8/8	2		P1

Frequencies

GnomAD3 genomes AF: 0.000783 AC: 119 AN: 152034 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

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: 0.00239

GnomAD3 exomes AF: 0.000326 AC: 82 AN: 251296 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135808

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.000347

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: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000124 AC: 181 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 78 AN XY: 727216

Gnomad4 AFR exome AF: 0.00427

Gnomad4 AMR exome AF: 0.000358

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: 0.00000270

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000789 AC: 120 AN: 152152 Hom.: 3 Cov.: 32 AF XY: 0.000847 AC XY: 63 AN XY: 74390

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.000720

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: 0.00237

Alfa AF: 0.000408 Hom.: 0

Bravo AF: 0.00125

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 17, 2017

- -

TRMT10A-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2022

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

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	6.4
Dann	Benign	0.57
DEOGEN2	Benign	0.0066	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.045	N
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0049	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.32	N;N;N
REVEL	Benign	0.0060
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.65	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.031
MVP		0.030
MPC		0.16
ClinPred		0.00078	T
GERP RS		-1.3
Varity_R		0.045
gMVP		0.17

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: rs143207059; hg19: chr4-100470310;