rs11879943

Positions:

• chr19-54192316-C-A
• chr19-54192316-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001077446.4(TSEN34):​c.688C>A​(p.Arg230=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,614,070 control chromosomes in the GnomAD database, including 734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (116 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (618 hom.)
• Consequence: TSEN34 NM_001077446.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.554

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-54192316-C-A is Benign according to our data. Variant chr19-54192316-C-A is described in ClinVar as [Benign]. Clinvar id is 137754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.554 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN34	NM_001077446.4	c.688C>A	p.Arg230=	synonymous_variant	3/4	ENST00000396388.3	NP_001070914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN34	ENST00000396388.3	c.688C>A	p.Arg230=	synonymous_variant	3/4	1	NM_001077446.4	ENSP00000379671	P2

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3617 AN: 152106 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0211 AC: 5246 AN: 249046 Hom.: 228 AF XY: 0.0178 AC XY: 2405 AN XY: 135188

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.0300

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.00369

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.00856 AC: 12510 AN: 1461846 Hom.: 618 Cov.: 35 AF XY: 0.00811 AC XY: 5898 AN XY: 727220

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: 0.0293

Gnomad4 NFE exome AF: 0.000622

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0238 AC: 3630 AN: 152224 Hom.: 116 Cov.: 32 AF XY: 0.0250 AC XY: 1864 AN XY: 74428

Gnomad4 AFR AF: 0.0509

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.0303

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00585 Hom.: 33

Bravo AF: 0.0258

Asia WGS AF: 0.0700 AC: 243 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2014	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pontoneocerebellar hypoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.51
CADD	Benign	8.7
DANN	Benign	0.81

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: rs11879943; hg19: chr19-54696167; COSMIC: COSV55475896; COSMIC: COSV55475896;