rs755184077

Variant names:

• chr14-60979582-CTATT-C
• rs755184077
• NM_020810.3:c.312_315delAATA

Your query was ambiguous. Multiple possible variants found:

• chr14-60979582-CTATT-C
• chr14-60979582-CTATT-CTATTTATT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_020810.3(TRMT5):​c.312_315delAATA​(p.Ile105SerfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.000902 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (0 hom.)
• Consequence: TRMT5 NM_020810.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:3
• Conservation: PhyloP100: 6.82
• Publications: 7 publications found

Genes affected

TRMT5 (HGNC:23141): (tRNA methyltransferase 5) tRNAs contain as many as 13 or 14 nucleotides that are modified posttranscriptionally by enzymes that are highly specific for particular nucleotides in the tRNA structure. TRMT5 methylates the N1 position of guanosine-37 (G37) in selected tRNAs using S-adenosyl methionine (Brule et al., 2004 [PubMed 15248782]).[supplied by OMIM, Mar 2008]

TRMT5 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation defect type 26

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000258892 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 14-60979582-CTATT-C is Pathogenic according to our data. Variant chr14-60979582-CTATT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372246.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020810.3. 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
	TRMT5	NM_020810.3	MANE Select	c.312_315delAATA	p.Ile105SerfsTer4	frameshift	Exon 2 of 5	NP_065861.3
	TRMT5	NM_001350253.1		c.396_399delAATA	p.Ile133SerfsTer4	frameshift	Exon 2 of 5	NP_001337182.1
	TRMT5	NM_001350254.1		c.393_396delAATA	p.Ile132SerfsTer4	frameshift	Exon 2 of 5	NP_001337183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT5	ENST00000261249.7	TSL:1 MANE Select	c.312_315delAATA	p.Ile105SerfsTer4	frameshift	Exon 2 of 5	ENSP00000261249.6
	TRMT5	ENST00000928589.1		c.312_315delAATA	p.Ile105SerfsTer4	frameshift	Exon 2 of 5	ENSP00000598648.1
	TRMT5	ENST00000553903.1	TSL:4	c.396_399delAATA	p.Ile133SerfsTer4	frameshift	Exon 2 of 2	ENSP00000452567.1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000867 AC: 218 AN: 251378 AF XY: 0.000979

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000910 AC: 1331 AN: 1461868 Hom.: 0 AF XY: 0.000873 AC XY: 635 AN XY: 727226

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 76 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86254

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53416

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00102 AC: 1132 AN: 1112000

Other (OTH) AF: 0.000993 AC: 60 AN: 60396

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74450

African (AFR) AF: 0.000120 AC: 5 AN: 41562

American (AMR) AF: 0.000589 AC: 9 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00135 AC: 92 AN: 68028

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.000733

EpiCase AF: 0.00153

EpiControl AF: 0.00142

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	-	-	Combined oxidative phosphorylation defect type 26 (5)
2	2	-	not provided (4)
-	1	-	not specified (1)
1	-	-	TRMT5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=5/195	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: rs755184077; hg19: chr14-61446300; COSMIC: COSV109406877; COSMIC: COSV109406877;