rs149081883

Variant names:

• chr11-64224653-C-G
• rs149081883
• NM_001033678.4:c.392G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-64224653-C-G
• chr11-64224653-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001033678.4(TRPT1):​c.392G>C​(p.Gly131Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,678 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. G131D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRPT1 NM_001033678.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.88
• Publications: 0 publications found

Genes affected

TRPT1 (HGNC:20316): (tRNA phosphotransferase 1) Predicted to enable tRNA 2'-phosphotransferase activity. Predicted to be involved in tRNA splicing, via endonucleolytic cleavage and ligation. Predicted to act upstream of or within regulation of protein kinase activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033678.4. 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
	TRPT1	NM_001033678.4	MANE Select	c.392G>C	p.Gly131Ala	missense	Exon 5 of 8	NP_001028850.2	Q86TN4-1
	TRPT1	NM_001160389.2		c.398G>C	p.Gly133Ala	missense	Exon 5 of 8	NP_001153861.1	Q86TN4-4
	TRPT1	NM_001160393.1		c.392G>C	p.Gly131Ala	missense	Exon 4 of 7	NP_001153865.1	Q86TN4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPT1	ENST00000317459.11	TSL:1 MANE Select	c.392G>C	p.Gly131Ala	missense	Exon 5 of 8	ENSP00000314073.6	Q86TN4-1
	TRPT1	ENST00000394547.7	TSL:1	c.245G>C	p.Gly82Ala	missense	Exon 4 of 7	ENSP00000378051.3	Q86TN4-2
	TRPT1	ENST00000394546.6	TSL:5	c.398G>C	p.Gly133Ala	missense	Exon 5 of 8	ENSP00000378050.2	Q86TN4-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455678 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723780

⚠️ 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: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 85354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108426

Other (OTH) AF: 0.00 AC: 0 AN: 60168

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		4.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.97		Gain of MoRF binding (P = 0.1463)
MVP		0.88
MPC		0.83
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.93
Mutation Taster		=33/67	disease causing

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: rs149081883; hg19: chr11-63992125;