rs587777744

Positions:

• chr4-99553814-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

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, single submitter P:3
• 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 Likely_pathogenic. Variant got 8 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_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT10A	NM_001134665.3	c.616G>A	p.Gly206Arg	missense_variant	6/8	ENST00000394876.7	NP_001128137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT10A	ENST00000394876.7	c.616G>A	p.Gly206Arg	missense_variant	6/8	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:3

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2014	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2023

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. -

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;