1-185139523-A-G

Position:

• chr1-185139523-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000367506.10(TRMT1L):​c.1166T>C​(p.Ile389Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I389V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRMT1L ENST00000367506.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.98

Genes affected

TRMT1L (HGNC:16782): (tRNA methyltransferase 1 like) This gene encodes a protein that has some similarity to N2,N2-dimethylguanosine tRNA methyltransferase from other organisms. Studies of the mouse ortholog have shown that this protein plays a role in motor coordination and exploratory behavior, and it may also be involved in modulating postnatal neuronal functions. Alternatively spliced transcripts have been identified for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT1L	NM_030934.5	c.1166T>C	p.Ile389Thr	missense_variant	9/15	ENST00000367506.10	NP_112196.3
TRMT1L	NM_001202423.2	c.698T>C	p.Ile233Thr	missense_variant	9/15		NP_001189352.1
TRMT1L	XM_047431291.1	c.698T>C	p.Ile233Thr	missense_variant	9/15		XP_047287247.1
TRMT1L	XM_047431292.1	c.698T>C	p.Ile233Thr	missense_variant	9/15		XP_047287248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT1L	ENST00000367506.10	c.1166T>C	p.Ile389Thr	missense_variant	9/15	1	NM_030934.5	ENSP00000356476	P1
TRMT1L	ENST00000458395.1	c.38T>C	p.Ile13Thr	missense_variant	1/4	3		ENSP00000414339

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.1166T>C (p.I389T) alteration is located in exon 9 (coding exon 9) of the TRMT1L gene. This alteration results from a T to C substitution at nucleotide position 1166, causing the isoleucine (I) at amino acid position 389 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0040	T
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.97	L;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.23
Sift	Benign	0.087	T;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.10	B;.
Vest4		0.80
MutPred		0.85		Loss of stability (P = 0.0292);.;
MVP		0.068
MPC		0.67
ClinPred		0.84	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs987822180; hg19: chr1-185108655;