chr19-54191458-A-C

Position:

• chr19-54191458-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001077446.4(TSEN34):​c.94A>C​(p.Thr32Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,395,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T32M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TSEN34 NM_001077446.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0430

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1662234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN34	NM_001077446.4	c.94A>C	p.Thr32Pro	missense_variant	1/4	ENST00000396388.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN34	ENST00000396388.3	c.94A>C	p.Thr32Pro	missense_variant	1/4	1	NM_001077446.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000422 AC: 6 AN: 142184 Hom.: 0 AF XY: 0.0000516 AC XY: 4 AN XY: 77568

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 14 AN: 1395726 Hom.: 0 Cov.: 35 AF XY: 0.0000116 AC XY: 8 AN XY: 688958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000251

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

ExAC AF: 0.0000196 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2021

The c.94A>C (p.T32P) alteration is located in exon 2 (coding exon 1) of the TSEN34 gene. This alteration results from a A to C substitution at nucleotide position 94, causing the threonine (T) at amino acid position 32 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2017

A variant of uncertain significance has been identified in the TSEN34 gene. The T32P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T32P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T32P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	.;T;T;.;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.24	N
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.3	.;.;L;.;L;L
MutationTaster	Benign	0.75	N;N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.1	N;N;N;.;N;N
REVEL	Benign	0.26
Sift	Benign	0.033	D;D;D;.;D;D
Sift4G	Benign	0.090	T;T;T;T;T;T
Polyphen		0.0030	.;.;B;.;B;B
Vest4		0.38, 0.28, 0.38, 0.22
MutPred		0.49		Gain of disorder (P = 0.0397);.;Gain of disorder (P = 0.0397);.;Gain of disorder (P = 0.0397);Gain of disorder (P = 0.0397);
MVP		0.54
MPC		0.37
ClinPred		0.084	T
GERP RS		3.0
Varity_R		0.70
gMVP		0.80

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: rs746020777; hg19: chr19-54695309;