1-39883356-G-A

Variant names:

• chr1-39883356-G-A
• rs747839263
• NM_017646.6:c.136C>T

Variant summary

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

The NM_017646.6(TRIT1):​c.136C>T​(p.Arg46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000493 in 1,459,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: TRIT1 NM_017646.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

Genes affected

TRIT1 (HGNC:20286): (tRNA isopentenyltransferase 1) This gene encodes a protein that that is targeted to the mitochondrion and modifies transfer RNAs (tRNAs) by adding a dimethylallyl group onto the adenine at position 37. This modification is important for maintaining the correct reading frame during protein translation. This gene is considered a tumor suppressor and its expression can decrease cell growth. Alternative splicing results in multiple transcripts variants, most of which are likely non-functional. [provided by RefSeq, Aug 2015]

MYCL-AS1 (HGNC:40386): (MYCL antisense RNA 1)

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 rank	MANE	Protein	UniProt
TRIT1	NM_017646.6	c.136C>T	p.Arg46Trp	missense_variant	Exon 1 of 11	ENST00000316891.10	NP_060116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIT1	ENST00000316891.10	c.136C>T	p.Arg46Trp	missense_variant	Exon 1 of 11	1	NM_017646.6	ENSP00000321810.5
TRIT1	ENST00000372818.5	c.136C>T	p.Arg46Trp	missense_variant	Exon 1 of 10	1		ENSP00000361905.1
TRIT1	ENST00000462797.5	n.136C>T		non_coding_transcript_exon_variant	Exon 1 of 10	5		ENSP00000473773.1
TRIT1	ENST00000486825.6	n.118C>T		non_coding_transcript_exon_variant	Exon 1 of 8	5		ENSP00000474151.1
TRIT1	ENST00000489945.5	n.136C>T		non_coding_transcript_exon_variant	Exon 1 of 7	5		ENSP00000473745.1
TRIT1	ENST00000492612.6	n.124C>T		non_coding_transcript_exon_variant	Exon 1 of 9	5		ENSP00000473708.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 244504 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133010

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000274

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1459958 Hom.: 0 Cov.: 30 AF XY: 0.0000386 AC XY: 28 AN XY: 726202

Gnomad4 AFR exome AF: 0.00

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: 0.0000630

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.136C>T (p.R46W) alteration is located in exon 1 (coding exon 1) of the TRIT1 gene. This alteration results from a C to T substitution at nucleotide position 136, causing the arginine (R) at amino acid position 46 to be replaced by a tryptophan (W). 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	0.14
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.3	M;M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.2	.;D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.61
MutPred		0.56		Loss of disorder (P = 0.0689);Loss of disorder (P = 0.0689);Loss of disorder (P = 0.0689);
MVP		0.68
MPC		0.71
ClinPred		0.99	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs747839263; hg19: chr1-40349028;