rs587777744

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000742321: 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)." and additional evidence is available in ClinVar.

• 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
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly, short stature, and impaired glucose metabolism 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• primary microcephaly-mild intellectual disability-young-onset diabetes syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000742321: 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).; SCV005758559: Experimental studies have shown that this missense change affects TRMT10A function (PMID: 25053765).
• 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 VariationId is 156230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134665.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT10A	NM_001134665.3	MANE Select	c.616G>A	p.Gly206Arg	missense	Exon 6 of 8	NP_001128137.1	Q8TBZ6
	TRMT10A	NM_001134666.3		c.616G>A	p.Gly206Arg	missense	Exon 6 of 8	NP_001128138.1	Q8TBZ6
	TRMT10A	NM_001375880.1		c.616G>A	p.Gly206Arg	missense	Exon 6 of 8	NP_001362809.1	Q8TBZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT10A	ENST00000394876.7	TSL:1 MANE Select	c.616G>A	p.Gly206Arg	missense	Exon 6 of 8	ENSP00000378342.2	Q8TBZ6
	TRMT10A	ENST00000273962.7	TSL:1	c.616G>A	p.Gly206Arg	missense	Exon 6 of 8	ENSP00000273962.3	Q8TBZ6
	TRMT10A	ENST00000394877.7	TSL:2	c.616G>A	p.Gly206Arg	missense	Exon 6 of 8	ENSP00000378343.3	Q8TBZ6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Microcephaly, short stature, and impaired glucose metabolism 1 (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.95		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777744; hg19: chr4-100474971;