NM_001136035.4:c.1876C>T

Variant names:

• chr19-13105039-G-A
• rs771237572
• NM_001136035.4:c.1876C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001136035.4(TRMT1):​c.1876C>T​(p.Pro626Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. P626T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRMT1 NM_001136035.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0700
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000304024 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08903816).

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.1876C>T	p.Pro626Ser	missense	Exon 17 of 17	NP_001129507.1	Q9NXH9-1
	TRMT1	NM_017722.5		c.1876C>T	p.Pro626Ser	missense	Exon 16 of 16	NP_060192.1	Q9NXH9-1
	TRMT1	NM_001142554.3		c.1789C>T	p.Pro597Ser	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.1876C>T	p.Pro626Ser	missense	Exon 17 of 17	ENSP00000350352.4	Q9NXH9-1
	TRMT1	ENST00000437766.5	TSL:1	c.1876C>T	p.Pro626Ser	missense	Exon 16 of 16	ENSP00000416149.1	Q9NXH9-1
	TRMT1	ENST00000221504.12	TSL:1	c.1789C>T	p.Pro597Ser	missense	Exon 15 of 15	ENSP00000221504.7	Q9NXH9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456710 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724272

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25632

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 85736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109154

Other (OTH) AF: 0.00 AC: 0 AN: 60198

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	10
DANN	Benign	0.87
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.070
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.016
Sift	Benign	0.21	T
Sift4G	Benign	0.61	T
Polyphen		0.0030	B
Vest4		0.25
MutPred		0.40		Gain of phosphorylation at P626 (P = 0.0567)
MVP		0.37
MPC		0.14
ClinPred		0.10	T
GERP RS		0.042
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.15
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs771237572; hg19: chr19-13215853; COSMIC: COSV105023092; COSMIC: COSV105023092;