rs77247739

chr17-75522247-A-Cchr17-75522247-A-T

Variant summary

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

The NM_207346.3(TSEN54):c.1166A>C(p.Gln389Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0945 in 1,547,262 control chromosomes in the GnomAD database, including 7,342 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q389H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.093 (711 hom., cov: 32)
  • Exomes 𝑓: 0.095 (6631 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.412

Genes affected

TSEN54 (HGNC:27561): (tRNA splicing endonuclease subunit 54) This gene encodes a subunit of the tRNA splicing endonuclease complex, which catalyzes the removal of introns from precursor tRNAs. The complex is also implicated in pre-mRNA 3-prime end processing. Mutations in this gene result in pontocerebellar hypoplasia type 2.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018183887).
• BP6: Variant 17-75522247-A-C is Benign according to our data. Variant chr17-75522247-A-C is described in ClinVar as [Benign]. Clinvar id is 96672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75522247-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN54	NM_207346.3	c.1166A>C	p.Gln389Pro	missense_variant	8/11	ENST00000333213.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN54	ENST00000333213.11	c.1166A>C	p.Gln389Pro	missense_variant	8/11	1	NM_207346.3	P1

Frequencies

GnomAD3 genomes AF: 0.0933 AC: 14199 AN: 152154 Hom.: 707 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0751

Gnomad ASJ AF: 0.0703

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0700

Gnomad FIN AF: 0.0796

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0937

GnomAD3 exomes AF: 0.0778 AC: 11366 AN: 146068 Hom.: 528 AF XY: 0.0778 AC XY: 6112 AN XY: 78546

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.0758

Gnomad EAS exome AF: 0.000748

Gnomad SAS exome AF: 0.0689

Gnomad FIN exome AF: 0.0816

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.0835

GnomAD4 exome AF: 0.0946 AC: 131976 AN: 1394990 Hom.: 6631 Cov.: 36 AF XY: 0.0938 AC XY: 64468 AN XY: 687646

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0527

Gnomad4 ASJ exome AF: 0.0769

Gnomad4 EAS exome AF: 0.000505

Gnomad4 SAS exome AF: 0.0680

Gnomad4 FIN exome AF: 0.0845

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0840

GnomAD4 genome AF: 0.0934 AC: 14217 AN: 152272 Hom.: 711 Cov.: 32 AF XY: 0.0910 AC XY: 6777 AN XY: 74442

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0749

Gnomad4 ASJ AF: 0.0703

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0696

Gnomad4 FIN AF: 0.0796

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.0937

Alfa AF: 0.0825 Hom.: 203

Bravo AF: 0.0924

TwinsUK AF: 0.105 AC: 390

ALSPAC AF: 0.0965 AC: 372

ESP6500AA AF: 0.0733 AC: 290

ESP6500EA AF: 0.0677 AC: 522

ExAC AF: 0.0333 AC: 2844

Asia WGS AF: 0.0530 AC: 184 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Pontoneocerebellar hypoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	5.8
Dann	Benign	0.40
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.067
Sift	Benign	0.17	T
Sift4G	Benign	0.24	T
Polyphen		0.13	B
Vest4		0.068
MPC		0.35
ClinPred		0.0039	T
GERP RS		-0.063
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.65

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: rs77247739; hg19: chr17-73518328; COSMIC: COSV51345330; COSMIC: COSV51345330;