rs184469579

Variant names:

• chr1-39883470-G-A
• rs184469579
• NM_017646.6:c.22C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-39883470-G-A
• chr1-39883470-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_017646.6(TRIT1):​c.22C>T​(p.Arg8*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,595,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: TRIT1 NM_017646.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 0.669
• Publications: 7 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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
• PP5: Variant 1-39883470-G-A is Pathogenic according to our data. Variant chr1-39883470-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 417684.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.22C>T	p.Arg8*	stop_gained	Exon 1 of 11	NP_060116.2
	TRIT1	NM_001312691.1		c.22C>T	p.Arg8*	stop_gained	Exon 1 of 10	NP_001299620.1	Q9H3H1-4
	TRIT1	NM_001312692.1		c.22C>T	p.Arg8*	stop_gained	Exon 1 of 9	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.22C>T	p.Arg8*	stop_gained	Exon 1 of 11	ENSP00000321810.5	Q9H3H1-1
	TRIT1	ENST00000372818.5	TSL:1	c.22C>T	p.Arg8*	stop_gained	Exon 1 of 10	ENSP00000361905.1	Q9H3H1-4
	TRIT1	ENST00000441669.6	TSL:1	c.22C>T	p.Arg8*	stop_gained	Exon 1 of 9	ENSP00000388333.2	Q9H3H1-5

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000173 AC: 42 AN: 242456 AF XY: 0.000196

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000569

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.000353 AC: 510 AN: 1443732 Hom.: 0 Cov.: 32 AF XY: 0.000333 AC XY: 238 AN XY: 714352

African (AFR) AF: 0.000121 AC: 4 AN: 33072

American (AMR) AF: 0.00 AC: 0 AN: 44248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39048

South Asian (SAS) AF: 0.00 AC: 0 AN: 85876

European-Finnish (FIN) AF: 0.000929 AC: 49 AN: 52722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.000394 AC: 433 AN: 1098006

Other (OTH) AF: 0.000388 AC: 23 AN: 59322

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15248

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Combined oxidative phosphorylation deficiency 35 (3)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
-	1	-	TRIT1 Deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.059
FATHMM_MKL	Benign	0.51	D
PhyloP100		0.67
Vest4		0.26
GERP RS		2.7
PromoterAI		-0.0064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=7/193	disease causing (ClinVar)

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: rs184469579; hg19: chr1-40349142;