1-185139524-T-C

Position:

• chr1-185139524-T-C

Variant summary

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

The NM_030934.5(TRMT1L):​c.1165A>G​(p.Ile389Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. I389T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRMT1L NM_030934.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

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.1165A>G	p.Ile389Val	missense_variant	9/15	ENST00000367506.10	NP_112196.3
TRMT1L	NM_001202423.2	c.697A>G	p.Ile233Val	missense_variant	9/15		NP_001189352.1
TRMT1L	XM_047431291.1	c.697A>G	p.Ile233Val	missense_variant	9/15		XP_047287247.1
TRMT1L	XM_047431292.1	c.697A>G	p.Ile233Val	missense_variant	9/15		XP_047287248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT1L	ENST00000367506.10	c.1165A>G	p.Ile389Val	missense_variant	9/15	1	NM_030934.5	ENSP00000356476.5
TRMT1L	ENST00000458395.1	c.37A>G	p.Ile13Val	missense_variant	1/4	3		ENSP00000414339.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461662 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727150

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Mar 01, 2023

The c.1165A>G (p.I389V) alteration is located in exon 9 (coding exon 9) of the TRMT1L gene. This alteration results from a A to G substitution at nucleotide position 1165, causing the isoleucine (I) at amino acid position 389 to be replaced by a valine (V). 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	Benign	0.063
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.46
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.00085	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.2	N;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.44	N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.085
MutPred		0.52		Gain of helix (P = 0.0325);.;
MVP		0.043
MPC		0.27
ClinPred		0.33	T
GERP RS		-0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs923049524; hg19: chr1-185108656;