rs536000212

Variant names:

• chr1-39854049-CG-C
• rs536000212
• NM_017646.6:c.334delC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_017646.6(TRIT1):​c.334delC​(p.Arg112GlufsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000718 in 1,609,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: TRIT1 NM_017646.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.33
• Publications: 4 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-39854049-CG-C is Pathogenic according to our data. Variant chr1-39854049-CG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 545453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017646.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIT1	NM_017646.6	MANE Select	c.334delC	p.Arg112GlufsTer36	frameshift	Exon 3 of 11	NP_060116.2
	TRIT1	NM_001312691.1		c.334delC	p.Arg112GlufsTer36	frameshift	Exon 3 of 10	NP_001299620.1	Q9H3H1-4
	TRIT1	NM_001312692.1		c.175-1174delC		intron	N/A	NP_001299621.1	Q9H3H1-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIT1	ENST00000316891.10	TSL:1 MANE Select	c.334delC	p.Arg112GlufsTer36	frameshift	Exon 3 of 11	ENSP00000321810.5	Q9H3H1-1
	TRIT1	ENST00000372818.5	TSL:1	c.334delC	p.Arg112GlufsTer36	frameshift	Exon 3 of 10	ENSP00000361905.1	Q9H3H1-4
	TRIT1	ENST00000441669.6	TSL:1	c.175-1174delC		intron	N/A	ENSP00000388333.2	Q9H3H1-5

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000427 AC: 106 AN: 248326 AF XY: 0.000484

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000691

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000758 AC: 1105 AN: 1457762 Hom.: 0 Cov.: 29 AF XY: 0.000736 AC XY: 534 AN XY: 725380

African (AFR) AF: 0.0000300 AC: 1 AN: 33302

American (AMR) AF: 0.000159 AC: 7 AN: 44040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.000549 AC: 47 AN: 85582

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000923 AC: 1025 AN: 1110008

Other (OTH) AF: 0.000398 AC: 24 AN: 60250

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74426

African (AFR) AF: 0.0000963 AC: 4 AN: 41538

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000564 Hom.: 0

Bravo AF: 0.000408

EpiCase AF: 0.000327

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Combined oxidative phosphorylation deficiency 35 (2)
2	-	-	not provided (2)
1	-	-	Epileptic encephalopathy (1)
1	-	-	See cases (1)
1	-	-	TRIT1 Deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs536000212; hg19: chr1-40319721; COSMIC: COSV109428035;