17-75516566-G-C

Variant names:

• chr17-75516566-G-C
• rs794726965
• NM_207346.3:c.6G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_207346.3(TSEN54):​c.6G>C​(p.Glu2Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,145,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E2E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000094 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.198
• Publications: 0 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 2A

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• pontocerebellar hypoplasia type 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11038941).

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.6G>C	p.Glu2Asp	missense	Exon 1 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.6G>C	p.Glu2Asp	missense	Exon 1 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.6G>C	p.Glu2Asp	missense	Exon 1 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.6G>C	p.Glu2Asp	missense	Exon 1 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.0000936 AC: 14 AN: 149578 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000502 AC: 5 AN: 996206 Hom.: 0 Cov.: 28 AF XY: 0.00000213 AC XY: 1 AN XY: 468866

African (AFR) AF: 0.000101 AC: 2 AN: 19780

American (AMR) AF: 0.00 AC: 0 AN: 5538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10668

East Asian (EAS) AF: 0.00 AC: 0 AN: 17348

South Asian (SAS) AF: 0.00 AC: 0 AN: 18794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2454

European-Non Finnish (NFE) AF: 0.00000231 AC: 2 AN: 867644

Other (OTH) AF: 0.0000267 AC: 1 AN: 37522

GnomAD4 genome AF: 0.0000936 AC: 14 AN: 149578 Hom.: 0 Cov.: 33 AF XY: 0.0000960 AC XY: 7 AN XY: 72918

African (AFR) AF: 0.000341 AC: 14 AN: 41090

American (AMR) AF: 0.00 AC: 0 AN: 15036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67070

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000140

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.71
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.25	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.20
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.038
Sift	Benign	0.16	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.048
MutPred		0.16		Loss of glycosylation at P3 (P = 0.0613)
MVP		0.45
MPC		0.23
ClinPred		0.15	T
GERP RS		0.76
PromoterAI		-0.029	Neutral
Varity_R		0.054
gMVP		0.14
Mutation Taster		=98/2	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: rs794726965; hg19: chr17-73512647;