19-13105031-TG-AA

Variant names:

• chr19-13105031-TG-AA
• NM_001136035.4:c.1883_1884delCAinsTT
• TRMT1 p.Thr628Ile

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001136035.4(TRMT1):​c.1883_1884delCAinsTT​(p.Thr628Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRMT1 NM_001136035.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.396
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.1883_1884delCAinsTT	p.Thr628Ile	missense	N/A	NP_001129507.1	Q9NXH9-1
	TRMT1	NM_017722.5		c.1883_1884delCAinsTT	p.Thr628Ile	missense	N/A	NP_060192.1	Q9NXH9-1
	TRMT1	NM_001142554.3		c.1796_1797delCAinsTT	p.Thr599Ile	missense	N/A	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.1883_1884delCAinsTT	p.Thr628Ile	missense	N/A	ENSP00000350352.4	Q9NXH9-1
	TRMT1	ENST00000437766.5	TSL:1	c.1883_1884delCAinsTT	p.Thr628Ile	missense	N/A	ENSP00000416149.1	Q9NXH9-1
	TRMT1	ENST00000221504.12	TSL:1	c.1796_1797delCAinsTT	p.Thr599Ile	missense	N/A	ENSP00000221504.7	Q9NXH9-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.40

Splicing

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

hg19: chr19-13215845;