rs2289145

Positions:

• chr19-54193391-G-A

Variant summary

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

The NM_001077446.4(TSEN34):​c.*29G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,613,706 control chromosomes in the GnomAD database, including 737 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (117 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (620 hom.)
• Consequence: TSEN34 NM_001077446.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.113

Genes affected

TSEN34 (HGNC:15506): (tRNA splicing endonuclease subunit 34) This gene encodes a catalytic subunit of the tRNA splicing endonuclease, which catalyzes the removal of introns from precursor tRNAs. The endonuclease complex is also associated with a pre-mRNA 3-prime end processing factor. A mutation in this gene results in the neurological disorder pontocerebellar hypoplasia type 2. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-54193391-G-A is Benign according to our data. Variant chr19-54193391-G-A is described in ClinVar as [Benign]. Clinvar id is 261679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN34	NM_001077446.4	c.*29G>A		3_prime_UTR_variant	4/4	ENST00000396388.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN34	ENST00000396388.3	c.*29G>A		3_prime_UTR_variant	4/4	1	NM_001077446.4	P2

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3625 AN: 152166 Hom.: 117 Cov.: 32

Gnomad AFR AF: 0.0509

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0211 AC: 5234 AN: 248252 Hom.: 226 AF XY: 0.0178 AC XY: 2401 AN XY: 134758

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.0299

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.135

Gnomad SAS exome AF: 0.00370

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.00856 AC: 12509 AN: 1461422 Hom.: 620 Cov.: 33 AF XY: 0.00811 AC XY: 5895 AN XY: 726970

Gnomad4 AFR exome AF: 0.0519

Gnomad4 AMR exome AF: 0.0287

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.00347

Gnomad4 FIN exome AF: 0.0292

Gnomad4 NFE exome AF: 0.000623

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0239 AC: 3638 AN: 152284 Hom.: 117 Cov.: 32 AF XY: 0.0250 AC XY: 1863 AN XY: 74460

Gnomad4 AFR AF: 0.0510

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.0302

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00668 Hom.: 33

Bravo AF: 0.0258

Asia WGS AF: 0.0700 AC: 243 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

Pontoneocerebellar hypoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.83
CADD	Benign	1.1
DANN	Benign	0.52

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: rs2289145; hg19: chr19-54697246; COSMIC: COSV55475902; COSMIC: COSV55475902;