19-54192316-C-A

Variant names:

• chr19-54192316-C-A
• rs11879943
• NM_001077446.4:c.688C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001077446.4(TSEN34):​c.688C>A​(p.Arg230Arg) 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
• Publications: 10 publications found

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]

TSEN34 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 2C

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
TSEN34	NM_001077446.4	c.688C>A	p.Arg230Arg	synonymous_variant	Exon 3 of 4	ENST00000396388.3	NP_001070914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSEN34	ENST00000396388.3	c.688C>A	p.Arg230Arg	synonymous_variant	Exon 3 of 4	1	NM_001077446.4	ENSP00000379671.2

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

GnomAD2 exomes AF: 0.0211 AC: 5246 AN: 249046 AF XY: 0.0178

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 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

African (AFR) AF: 0.0519 AC: 1738 AN: 33476

American (AMR) AF: 0.0287 AC: 1284 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26136

East Asian (EAS) AF: 0.151 AC: 5995 AN: 39700

South Asian (SAS) AF: 0.00347 AC: 299 AN: 86256

European-Finnish (FIN) AF: 0.0293 AC: 1565 AN: 53420

Middle Eastern (MID) AF: 0.00314 AC: 18 AN: 5736

European-Non Finnish (NFE) AF: 0.000622 AC: 692 AN: 1112008

Other (OTH) AF: 0.0141 AC: 849 AN: 60390

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

African (AFR) AF: 0.0509 AC: 2114 AN: 41526

American (AMR) AF: 0.0184 AC: 281 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.131 AC: 679 AN: 5166

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4830

European-Finnish (FIN) AF: 0.0303 AC: 322 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68016

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0116 Hom.: 76

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

Apr 15, 2014

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 13, 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	-0.51
CADD	Benign	8.7
DANN	Benign	0.81
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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