chr19-54191869-C-T

Variant names:

• chr19-54191869-C-T
• rs202245444
• NM_001077446.4:c.392C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001077446.4(TSEN34):​c.392C>T​(p.Ser131Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000556 in 1,614,086 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: TSEN34 NM_001077446.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.469
• Publications: 5 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01004678).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077446.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	NM_001077446.4	MANE Select	c.392C>T	p.Ser131Leu	missense	Exon 2 of 4	NP_001070914.1
	TSEN34	NM_001282333.2		c.392C>T	p.Ser131Leu	missense	Exon 3 of 6	NP_001269262.2
	TSEN34	NM_001282332.2		c.392C>T	p.Ser131Leu	missense	Exon 3 of 5	NP_001269261.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	ENST00000396388.3	TSL:1 MANE Select	c.392C>T	p.Ser131Leu	missense	Exon 2 of 4	ENSP00000379671.2
	TSEN34	ENST00000302937.8	TSL:1	c.392C>T	p.Ser131Leu	missense	Exon 3 of 5	ENSP00000305524.4
	TSEN34	ENST00000396383.5	TSL:1	c.392C>T	p.Ser131Leu	missense	Exon 3 of 5	ENSP00000379667.1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000538 AC: 134 AN: 249300 AF XY: 0.000517

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000743

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000558 AC: 816 AN: 1461878 Hom.: 1 Cov.: 35 AF XY: 0.000560 AC XY: 407 AN XY: 727240

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.00130 AC: 58 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000629 AC: 700 AN: 1112000

Other (OTH) AF: 0.000646 AC: 39 AN: 60392

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74414

African (AFR) AF: 0.000289 AC: 12 AN: 41528

American (AMR) AF: 0.000785 AC: 12 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000604 Hom.: 0

Bravo AF: 0.000657

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000607 AC: 5

ExAC AF: 0.000438 AC: 53

EpiCase AF: 0.00120

EpiControl AF: 0.00130

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	not specified (1)
-	1	-	Pontocerebellar hypoplasia type 2C (1)
-	1	-	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.47
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.048
Sift	Benign	0.16	T
Sift4G	Benign	0.29	T
Polyphen		0.020	B
Vest4		0.19
MVP		0.57
MPC		0.26
ClinPred		0.011	T
GERP RS		2.1
Varity_R		0.053
gMVP		0.34
Mutation Taster		=95/5	polymorphism

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: rs202245444; hg19: chr19-54695720;