19-13105032-G-C

Variant names:

• chr19-13105032-G-C
• rs577720271
• NM_001136035.4:c.1883C>G
• TRMT1 p.Thr628Arg

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001136035.4(TRMT1):​c.1883C>G​(p.Thr628Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T628I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRMT1 NM_001136035.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.396
• Publications: 2 publications found

Genes affected

TRMT1 (HGNC:25980): (tRNA methyltransferase 1) This gene encodes a tRNA-modifying enzyme that acts as a dimethyltransferase, modifying a single guanine residue at position 26 of the tRNA. The encoded enzyme has both mono- and dimethylase activity when exogenously expressed, and uses S-adenosyl methionine as a methyl donor. The C-terminal region of the encoded protein has both a zinc finger motif, and an arginine/proline-rich region. Mutations in this gene have been implicated in autosomal recessive intellectual disorder (ARID). Alternative splicing results in multiple transcript variants encoding different isoforms. There is a pseudogene of this gene on the X chromosome. [provided by RefSeq, May 2017]

TRMT1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 68

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000304024 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06498891).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136035.4. 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
	TRMT1	NM_001136035.4	MANE Select	c.1883C>G	p.Thr628Arg	missense	Exon 17 of 17	NP_001129507.1	Q9NXH9-1
	TRMT1	NM_017722.5		c.1883C>G	p.Thr628Arg	missense	Exon 16 of 16	NP_060192.1	Q9NXH9-1
	TRMT1	NM_001142554.3		c.1796C>G	p.Thr599Arg	missense	Exon 15 of 15	NP_001136026.1	Q9NXH9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT1	ENST00000357720.9	TSL:2 MANE Select	c.1883C>G	p.Thr628Arg	missense	Exon 17 of 17	ENSP00000350352.4	Q9NXH9-1
	TRMT1	ENST00000437766.5	TSL:1	c.1883C>G	p.Thr628Arg	missense	Exon 16 of 16	ENSP00000416149.1	Q9NXH9-1
	TRMT1	ENST00000221504.12	TSL:1	c.1796C>G	p.Thr599Arg	missense	Exon 15 of 15	ENSP00000221504.7	Q9NXH9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.8
DANN	Benign	0.84
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.40
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.015
Sift	Benign	0.072	T
Sift4G	Benign	0.17	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.17
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs577720271; hg19: chr19-13215846;