rs200434678

Variant names:

• chr17-75522195-G-A
• rs200434678
• NM_207346.3:c.1114G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_207346.3(TSEN54):​c.1114G>A​(p.Val372Met) variant causes a missense change. The variant allele was found at a frequency of 0.00055 in 1,550,716 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (2 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 7.09
• Publications: 5 publications found

Genes affected

TSEN54 (HGNC:27561): (tRNA splicing endonuclease subunit 54) This gene encodes a subunit of the tRNA splicing endonuclease complex, which catalyzes the removal of introns from precursor tRNAs. The complex is also implicated in pre-mRNA 3-prime end processing. Mutations in this gene result in pontocerebellar hypoplasia type 2.[provided by RefSeq, Oct 2009]

TSEN54 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pontocerebellar hypoplasia type 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207346.3. 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
	TSEN54	NM_207346.3	MANE Select	c.1114G>A	p.Val372Met	missense	Exon 8 of 11	NP_997229.2	Q7Z6J9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	ENST00000333213.11	TSL:1 MANE Select	c.1114G>A	p.Val372Met	missense	Exon 8 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.1114G>A	p.Val372Met	missense	Exon 8 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.1114G>A	p.Val372Met	missense	Exon 8 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000469 AC: 74 AN: 157756 AF XY: 0.000487

Gnomad AFR exome AF: 0.000232

Gnomad AMR exome AF: 0.000195

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000389

Gnomad NFE exome AF: 0.000791

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000561 AC: 784 AN: 1398402 Hom.: 2 Cov.: 72 AF XY: 0.000572 AC XY: 394 AN XY: 689028

African (AFR) AF: 0.000253 AC: 8 AN: 31608

American (AMR) AF: 0.000272 AC: 10 AN: 36776

Ashkenazi Jewish (ASJ) AF: 0.000239 AC: 6 AN: 25112

East Asian (EAS) AF: 0.0000558 AC: 2 AN: 35828

South Asian (SAS) AF: 0.000554 AC: 44 AN: 79360

European-Finnish (FIN) AF: 0.000393 AC: 19 AN: 48310

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5666

European-Non Finnish (NFE) AF: 0.000599 AC: 646 AN: 1077832

Other (OTH) AF: 0.000708 AC: 41 AN: 57910

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41570

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000800 Hom.: 0

Bravo AF: 0.000400

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000232 AC: 1

ESP6500EA AF: 0.000595 AC: 5

ExAC AF: 0.000396 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	1	not provided (7)
-	1	-	Inborn genetic diseases (1)
-	1	-	Olivopontocerebellar hypoplasia (1)
-	1	-	Pontocerebellar hypoplasia type 2A;C1856974:Pontocerebellar hypoplasia type 4;C1857762:Pontocerebellar hypoplasia type 5 (1)
-	1	-	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.095	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.050	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MVP		0.76
MPC		0.92
ClinPred		0.073	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.52
Mutation Taster		=84/16	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: rs200434678; hg19: chr17-73518276; COSMIC: COSV99390802; COSMIC: COSV99390802;