1-184051777-G-C

Position:

• chr1-184051777-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052965.4(TSEN15):​c.22G>C​(p.Glu8Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSEN15 NM_052965.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.101

Genes affected

TSEN15 (HGNC:16791): (tRNA splicing endonuclease subunit 15) This gene encodes a subunit of the tRNA splicing endonuclease, which catalyzes the removal of introns from tRNA precursors. Alternative splicing results in multiple transcript variants. There is a pseudogene of this gene on chromosome 17. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053907007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN15	NM_052965.4	c.22G>C	p.Glu8Gln	missense_variant	1/5	ENST00000645668.2	NP_443197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN15	ENST00000645668.2	c.22G>C	p.Glu8Gln	missense_variant	1/5		NM_052965.4	ENSP00000493902	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000378 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.22G>C (p.E8Q) alteration is located in exon 1 (coding exon 1) of the TSEN15 gene. This alteration results from a G to C substitution at nucleotide position 22, causing the glutamic acid (E) at amino acid position 8 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.0059	T;.;.;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.68	T;T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.054	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N;N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.75	.;N;N;.;N;.;.
REVEL	Benign	0.046
Sift	Benign	0.26	.;T;T;.;T;.;.
Sift4G	Benign	0.30	.;T;T;.;T;.;.
Polyphen		0.0010	B;.;.;.;.;.;.
Vest4		0.12, 0.17, 0.13
MutPred		0.13		Loss of solvent accessibility (P = 0.1868);Loss of solvent accessibility (P = 0.1868);Loss of solvent accessibility (P = 0.1868);Loss of solvent accessibility (P = 0.1868);Loss of solvent accessibility (P = 0.1868);Loss of solvent accessibility (P = 0.1868);Loss of solvent accessibility (P = 0.1868);
MVP		0.20
MPC		0.48
ClinPred		0.17	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.12

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: rs1445474819; hg19: chr1-184020911;