1-39841915-T-C

Variant names:

• chr1-39841915-T-C
• NM_017646.6:c.1235-2A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_017646.6(TRIT1):​c.1235-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000069 in 1,449,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRIT1 NM_017646.6 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.71

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 2.7094016 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-39841915-T-C is Pathogenic according to our data. Variant chr1-39841915-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2585517.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIT1	NM_017646.6	c.1235-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 10	ENST00000316891.10	NP_060116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIT1	ENST00000316891.10	c.1235-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 10	1	NM_017646.6	ENSP00000321810.5
TRIT1	ENST00000372818.5	c.1157-2A>G		splice_acceptor_variant, intron_variant	Intron 9 of 9	1		ENSP00000361905.1
TRIT1	ENST00000462797.5	n.*75-2A>G		splice_acceptor_variant, intron_variant	Intron 9 of 9	5		ENSP00000473773.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449282 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720544

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation deficiency 35 Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The splice acceptor c.1235-2A>G variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1235-2A>G variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has not been reported to the ClinVar database. The c.1235-2A>G variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of other reportable variant, the molecular diagnosis is not confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: -40
DS_AL_spliceai		0.99		Position offset: -2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-40307587;