1-39842047-A-T

Variant names:

• chr1-39842047-A-T
• rs230310
• NM_017646.6:c.1235-134T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017646.6(TRIT1):​c.1235-134T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 806,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: TRIT1 NM_017646.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.293
• Publications: 9 publications found

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]

TRIT1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation deficiency 35

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIT1	NM_017646.6	c.1235-134T>A		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.1235-134T>A		intron_variant	Intron 10 of 10	1	NM_017646.6	ENSP00000321810.5
TRIT1	ENST00000372818.5	c.1157-134T>A		intron_variant	Intron 9 of 9	1		ENSP00000361905.1
TRIT1	ENST00000462797.5	n.*75-134T>A		intron_variant	Intron 9 of 9	5		ENSP00000473773.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000124 AC: 1 AN: 806658 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 408334

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18358

American (AMR) AF: 0.00 AC: 0 AN: 18334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15838

East Asian (EAS) AF: 0.00 AC: 0 AN: 32236

South Asian (SAS) AF: 0.00 AC: 0 AN: 51638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3496

European-Non Finnish (NFE) AF: 0.00000168 AC: 1 AN: 596078

Other (OTH) AF: 0.00 AC: 0 AN: 37546

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 86333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.4
DANN	Benign	0.77
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs230310; hg19: chr1-40307719;