chr17-75522040-C-T

Variant names:

• chr17-75522040-C-T
• rs189860274
• NM_207346.3:c.959C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_207346.3(TSEN54):​c.959C>T​(p.Pro320Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000527 in 1,591,618 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P320R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.56
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070281625).
• BP6: Variant 17-75522040-C-T is Benign according to our data. Variant chr17-75522040-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00275 (419/152374) while in subpopulation AFR AF = 0.0093 (387/41598). AF 95% confidence interval is 0.00854. There are 4 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.959C>T	p.Pro320Leu	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.959C>T	p.Pro320Leu	missense	Exon 8 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.959C>T	p.Pro320Leu	missense	Exon 8 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.959C>T	p.Pro320Leu	missense	Exon 8 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152256 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00933

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000837 AC: 172 AN: 205488 AF XY: 0.000718

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000566

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 0.000292 AC: 420 AN: 1439244 Hom.: 2 Cov.: 31 AF XY: 0.000241 AC XY: 172 AN XY: 714070

African (AFR) AF: 0.0104 AC: 343 AN: 32848

American (AMR) AF: 0.00100 AC: 42 AN: 41830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25676

East Asian (EAS) AF: 0.00 AC: 0 AN: 38338

South Asian (SAS) AF: 0.00 AC: 0 AN: 83198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50458

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.00000545 AC: 6 AN: 1101628

Other (OTH) AF: 0.000454 AC: 27 AN: 59524

GnomAD4 genome AF: 0.00275 AC: 419 AN: 152374 Hom.: 4 Cov.: 32 AF XY: 0.00260 AC XY: 194 AN XY: 74518

African (AFR) AF: 0.00930 AC: 387 AN: 41598

American (AMR) AF: 0.00163 AC: 25 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000710 Hom.: 1

Bravo AF: 0.00331

ESP6500AA AF: 0.0105 AC: 46

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000813 AC: 98

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	not specified (1)
-	-	1	TSEN54-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.038	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.16
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.25
MVP		0.69
MPC		0.92
ClinPred		0.056	T
GERP RS		5.2
Varity_R		0.14
gMVP		0.30
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs189860274; hg19: chr17-73518121; COSMIC: COSV99031770; COSMIC: COSV99031770;