1-39847628-A-G

Variant names:

• chr1-39847628-A-G
• rs199622789
• NM_017646.6:c.848T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_017646.6(TRIT1):​c.848T>C​(p.Ile283Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I283S) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TRIT1 NM_017646.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.90

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-39847628-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 417681.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIT1	NM_017646.6	c.848T>C	p.Ile283Thr	missense_variant	Exon 7 of 11	ENST00000316891.10	NP_060116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIT1	ENST00000316891.10	c.848T>C	p.Ile283Thr	missense_variant	Exon 7 of 11	1	NM_017646.6	ENSP00000321810.5
TRIT1	ENST00000372818.5	c.848T>C	p.Ile283Thr	missense_variant	Exon 7 of 10	1		ENSP00000361905.1
TRIT1	ENST00000462797.5	n.848T>C		non_coding_transcript_exon_variant	Exon 7 of 10	5		ENSP00000473773.1
TRIT1	ENST00000469476.2	n.*226T>C		non_coding_transcript_exon_variant	Exon 6 of 6	5		ENSP00000474768.1
TRIT1	ENST00000486825.6	n.*508T>C		non_coding_transcript_exon_variant	Exon 7 of 8	5		ENSP00000474151.1
TRIT1	ENST00000489945.5	n.*266T>C		non_coding_transcript_exon_variant	Exon 6 of 7	5		ENSP00000473745.1
TRIT1	ENST00000492612.6	n.*270T>C		non_coding_transcript_exon_variant	Exon 6 of 9	5		ENSP00000473708.1
TRIT1	ENST00000469476.2	n.*226T>C		3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000474768.1
TRIT1	ENST00000486825.6	n.*508T>C		3_prime_UTR_variant	Exon 7 of 8	5		ENSP00000474151.1
TRIT1	ENST00000489945.5	n.*266T>C		3_prime_UTR_variant	Exon 6 of 7	5		ENSP00000473745.1
TRIT1	ENST00000492612.6	n.*270T>C		3_prime_UTR_variant	Exon 6 of 9	5		ENSP00000473708.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251374 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	4.3	.;H;H
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.6	.;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.98
MVP		0.88
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs199622789; hg19: chr1-40313300;