rs8074291

Variant names:

• chr17-75517075-G-A
• rs8074291
• NM_207346.3:c.285+3G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_207346.3(TSEN54):​c.285+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,592,506 control chromosomes in the GnomAD database, including 17,672 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3402 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14270 hom.)
• Consequence: TSEN54 NM_207346.3 splice_region, intron
• Scores: Splicing: ADA: 0.001151
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.36
• Publications: 11 publications found

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]

TSEN54 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 2A

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• pontocerebellar hypoplasia type 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
• pontocerebellar hypoplasia type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 17-75517075-G-A is Benign according to our data. Variant chr17-75517075-G-A is described in ClinVar as Benign. ClinVar VariationId is 137755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSEN54	NM_207346.3	c.285+3G>A		splice_region_variant, intron_variant	Intron 3 of 10	ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11	c.285+3G>A		splice_region_variant, intron_variant	Intron 3 of 10	1	NM_207346.3	ENSP00000327487.6

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28151 AN: 152100 Hom.: 3392 Cov.: 33

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0207

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.129 AC: 27006 AN: 209186 AF XY: 0.127

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.0874

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.0181

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.134 AC: 193417 AN: 1440288 Hom.: 14270 Cov.: 54 AF XY: 0.133 AC XY: 94938 AN XY: 714632

African (AFR) AF: 0.350 AC: 11576 AN: 33088

American (AMR) AF: 0.0900 AC: 3752 AN: 41706

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4264 AN: 25718

East Asian (EAS) AF: 0.0181 AC: 703 AN: 38758

South Asian (SAS) AF: 0.0989 AC: 8231 AN: 83232

European-Finnish (FIN) AF: 0.114 AC: 5740 AN: 50260

Middle Eastern (MID) AF: 0.157 AC: 898 AN: 5726

European-Non Finnish (NFE) AF: 0.136 AC: 150102 AN: 1102258

Other (OTH) AF: 0.137 AC: 8151 AN: 59542

GnomAD4 genome AF: 0.185 AC: 28198 AN: 152218 Hom.: 3402 Cov.: 33 AF XY: 0.181 AC XY: 13502 AN XY: 74418

African (AFR) AF: 0.337 AC: 13992 AN: 41522

American (AMR) AF: 0.133 AC: 2041 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 567 AN: 3472

East Asian (EAS) AF: 0.0203 AC: 105 AN: 5166

South Asian (SAS) AF: 0.101 AC: 490 AN: 4830

European-Finnish (FIN) AF: 0.108 AC: 1149 AN: 10604

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9401 AN: 68000

Other (OTH) AF: 0.178 AC: 377 AN: 2114

Alfa AF: 0.159 Hom.: 1058

Bravo AF: 0.192

Asia WGS AF: 0.0890 AC: 313 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pontoneocerebellar hypoplasia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.95
PhyloP100		2.4
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.010
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: rs8074291; hg19: chr17-73513156; COSMIC: COSV58691261; COSMIC: COSV58691261;