chr4-99549153-G-T

Position:

chr4-99549153-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 15/21 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.522

Variant links:

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]

TRMT10A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=1, 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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.000783

AC:

119

AN:

152034

Hom.:

Cov.:

show subpopulations

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:

AN:

251296

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135808

show subpopulations

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.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727216

show subpopulations

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.:

Cov.:

AF XY:

0.000847

AC XY:

AN XY:

74390

show subpopulations

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.:

Bravo

AF:

0.00125

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000346

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

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 disorder

Benign:1

Likely benign, no assertion criteria provided

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.68

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

LIST_S2

Benign

0.54

.;.;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.0049

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.23

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over