rs1046934

Positions:

• chr1-184054395-A-C
• chr1-184054395-A-G
• chr1-184054395-A-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.177A>C​(p.Gln59His) 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 1,603,524 control chromosomes in the GnomAD database, including 93,647 homozygotes. In-silico tool predicts 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 (6992 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86655 hom.)
• Consequence: TSEN15 NM_052965.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.78

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=0.0030647218).
• BP6: Variant 1-184054395-A-C is Benign according to our data. Variant chr1-184054395-A-C is described in ClinVar as [Benign]. Clinvar id is 1284754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-184054395-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN15	NM_052965.4	c.177A>C	p.Gln59His	missense_variant	2/5	ENST00000645668.2	NP_443197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN15	ENST00000645668.2	c.177A>C	p.Gln59His	missense_variant	2/5		NM_052965.4	ENSP00000493902	P3

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43936 AN: 151898 Hom.: 6993 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.281

GnomAD3 exomes AF: 0.335 AC: 83944 AN: 250454 Hom.: 15007 AF XY: 0.338 AC XY: 45754 AN XY: 135338

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.489

Gnomad SAS exome AF: 0.333

Gnomad FIN exome AF: 0.416

Gnomad NFE exome AF: 0.343

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.340 AC: 494027 AN: 1451508 Hom.: 86655 Cov.: 30 AF XY: 0.340 AC XY: 245664 AN XY: 722494

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.300

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.459

Gnomad4 SAS exome AF: 0.331

Gnomad4 FIN exome AF: 0.415

Gnomad4 NFE exome AF: 0.345

Gnomad4 OTH exome AF: 0.327

GnomAD4 genome AF: 0.289 AC: 43948 AN: 152016 Hom.: 6992 Cov.: 32 AF XY: 0.293 AC XY: 21784 AN XY: 74302

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.335

Gnomad4 FIN AF: 0.416

Gnomad4 NFE AF: 0.343

Gnomad4 OTH AF: 0.281

Alfa AF: 0.323 Hom.: 20127

Bravo AF: 0.274

TwinsUK AF: 0.347 AC: 1286

ALSPAC AF: 0.352 AC: 1357

ESP6500AA AF: 0.163 AC: 717

ESP6500EA AF: 0.348 AC: 2989

ExAC AF: 0.335 AC: 40650

Asia WGS AF: 0.366 AC: 1276 AN: 3476

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	clinical testing	GeneDx	Jul 15, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.;.;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.70	T;T;T;T;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.;.
MutationTaster	Benign	0.00043	P;P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.2	.;D;D;.;D;.;.
REVEL	Benign	0.094
Sift	Pathogenic	0.0	.;D;D;.;D;.;.
Sift4G	Uncertain	0.010	.;D;D;.;D;.;.
Polyphen		0.0020	B;.;.;.;.;.;.
Vest4		0.32, 0.15, 0.29
MutPred		0.30		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MPC		0.48
ClinPred		0.066	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1046934; hg19: chr1-184023529; COSMIC: COSV62294146;