rs2274432

Positions:

• chr1-184051811-G-A
• chr1-184051811-G-C
• chr1-184051811-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052965.4(TSEN15):​c.56G>A​(p.Gly19Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,539,678 control chromosomes in the GnomAD database, including 89,053 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (6955 hom., cov: 32)
  • Exomes 𝑓: 0.34 (82098 hom.)
• Consequence: TSEN15 NM_052965.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.161

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4963746E-4).
• BP6: Variant 1-184051811-G-A is Benign according to our data. Variant chr1-184051811-G-A is described in ClinVar as [Benign]. Clinvar id is 1249884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-184051811-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN15	NM_052965.4	c.56G>A	p.Gly19Asp	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.56G>A	p.Gly19Asp	missense_variant	1/5		NM_052965.4	ENSP00000493902	P3

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43806 AN: 151964 Hom.: 6956 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.281

GnomAD3 exomes AF: 0.332 AC: 46256 AN: 139146 Hom.: 8295 AF XY: 0.336 AC XY: 25156 AN XY: 74840

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.297

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.492

Gnomad SAS exome AF: 0.333

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.340

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.340 AC: 471744 AN: 1387596 Hom.: 82098 Cov.: 35 AF XY: 0.340 AC XY: 232462 AN XY: 684630

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.298

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.452

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.412

Gnomad4 NFE exome AF: 0.345

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.288 AC: 43818 AN: 152082 Hom.: 6955 Cov.: 32 AF XY: 0.292 AC XY: 21726 AN XY: 74348

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.414

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.281

Alfa AF: 0.326 Hom.: 18093

Bravo AF: 0.273

TwinsUK AF: 0.347 AC: 1287

ALSPAC AF: 0.352 AC: 1356

ESP6500AA AF: 0.136 AC: 552

ESP6500EA AF: 0.296 AC: 2369

ExAC AF: 0.220 AC: 19829

Asia WGS AF: 0.366 AC: 1278 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	This variant is associated with the following publications: (PMID: 18391951) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0093	T;.;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.56	T;T;T;T;T;T;T
MetaRNN	Benign	0.00015	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L;L;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	.;N;N;.;N;.;.
REVEL	Benign	0.16
Sift	Benign	0.035	.;D;T;.;T;.;.
Sift4G	Uncertain	0.022	.;D;D;.;D;.;.
Polyphen		0.0	B;.;.;.;.;.;.
Vest4		0.14, 0.072, 0.13
MPC		0.75
ClinPred		0.0038	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.18

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: rs2274432; hg19: chr1-184020945; COSMIC: COSV62294595; COSMIC: COSV62294595;