chr4-99553814-C-T

Variant names:

• chr4-99553814-C-T
• rs587777744
• NM_001134665.3:c.616G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001134665.3(TRMT10A):​c.616G>A​(p.Gly206Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRMT10A NM_001134665.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.23

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 4-99553814-C-T is Pathogenic according to our data. Variant chr4-99553814-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 156230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMT10A	NM_001134665.3	c.616G>A	p.Gly206Arg	missense_variant	Exon 6 of 8	ENST00000394876.7	NP_001128137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRMT10A	ENST00000394876.7	c.616G>A	p.Gly206Arg	missense_variant	Exon 6 of 8	1	NM_001134665.3	ENSP00000378342.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, short stature, and impaired glucose metabolism 1 Pathogenic:2

Sep 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Oct 26, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.616G>A (p.G206R) alteration is located in coding exon 5 of the TRMT10A gene. This alteration results from a G to A substitution at nucleotide position 616, causing the glycine (G) at amino acid position 206 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been previously reported in homozygous form in three siblings from a Jewish community in Uzbekistan. At the time of reporting, the siblings were 19 (female), 14 (male) and 13 (male) years of age. All three siblings had microcephaly, developmental delays and intellectual disability, short stature, and altered glucose metabolism including episodes of hypoglycemia, hyperinsulinemia and abnormal response to glucose. They also had a low birth weight and experienced recurrent seizures from 5 to 6 years of age with normal EEG findings. The female patient had delayed puberty and was amenorrheic at the time of reporting (Gillis, 2014). This variant has also been reported in homozygous form in an 11 year old Jewish female with diabetes, intellectual disability, developmental delay, bilateral hypoplastic kidneys, short stature, microcephaly, and dysmorphic features. This child was also noted to have IUGR during the pregnancy (Stern, 2022). This amino acid position is highly conserved in available vertebrate species. Authors performed in vitro functional studies with purified mutant p.G206R TRMT10A protein. Although binding of the mutant protein to a known tRNA substrate was similar to wild type, methylation studies showed almost complete loss of its methyltransferase activity. Gillis (2014) performed additional studies on this alteration using the yeast homolog, Trm10, and showed a significant reduction in the ability of the mutant protein to bind to the S-adenosyl methionine methyl donor. It was hypothesized that the loss of methyltransferase activity of the mutant enzyme is the result of its inability to bind to the methyl donor substrate (Gillis, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 206 of the TRMT10A protein (p.Gly206Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TRMT10A-related conditions (PMID: 25053765, 35137278). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156230). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TRMT10A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TRMT10A function (PMID: 25053765). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.3	H;H;H
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.7	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.98
MutPred		0.95		Gain of glycosylation at Y203 (P = 0.0455);Gain of glycosylation at Y203 (P = 0.0455);Gain of glycosylation at Y203 (P = 0.0455);
MVP		0.82
MPC		0.69
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.96

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: rs587777744; hg19: chr4-100474971;