chr17-75523332-C-T

Variant names:

• chr17-75523332-C-T
• rs8064529
• NM_207346.3:c.1310C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207346.3(TSEN54):​c.1310C>T​(p.Ala437Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,613,570 control chromosomes in the GnomAD database, including 372,403 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A437D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.64 (31161 hom., cov: 31)
  • Exomes 𝑓: 0.68 (341242 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.442
• Publications: 48 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=4.8462252E-6).
• BP6: Variant 17-75523332-C-T is Benign according to our data. Variant chr17-75523332-C-T is described in ClinVar as Benign. ClinVar VariationId is 160127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

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.1310C>T	p.Ala437Val	missense	Exon 9 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.1310C>T	p.Ala437Val	missense	Exon 9 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.1523C>T	p.Ala508Val	missense	Exon 9 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.1466C>T	p.Ala489Val	missense	Exon 9 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96395 AN: 151732 Hom.: 31158 Cov.: 31

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.622

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.627

GnomAD2 exomes AF: 0.617 AC: 155045 AN: 251440 AF XY: 0.632

Gnomad AFR exome AF: 0.582

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.592

Gnomad EAS exome AF: 0.439

Gnomad FIN exome AF: 0.698

Gnomad NFE exome AF: 0.692

Gnomad OTH exome AF: 0.634

GnomAD4 exome AF: 0.679 AC: 992514 AN: 1461720 Hom.: 341242 Cov.: 55 AF XY: 0.680 AC XY: 494720 AN XY: 727174

African (AFR) AF: 0.568 AC: 19023 AN: 33472

American (AMR) AF: 0.404 AC: 18089 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 15503 AN: 26134

East Asian (EAS) AF: 0.453 AC: 17987 AN: 39698

South Asian (SAS) AF: 0.667 AC: 57517 AN: 86256

European-Finnish (FIN) AF: 0.697 AC: 37212 AN: 53368

Middle Eastern (MID) AF: 0.639 AC: 3687 AN: 5766

European-Non Finnish (NFE) AF: 0.705 AC: 784003 AN: 1111916

Other (OTH) AF: 0.654 AC: 39493 AN: 60388

GnomAD4 genome AF: 0.635 AC: 96426 AN: 151850 Hom.: 31161 Cov.: 31 AF XY: 0.633 AC XY: 46956 AN XY: 74190

African (AFR) AF: 0.579 AC: 23955 AN: 41362

American (AMR) AF: 0.508 AC: 7749 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2101 AN: 3466

East Asian (EAS) AF: 0.456 AC: 2359 AN: 5168

South Asian (SAS) AF: 0.647 AC: 3109 AN: 4802

European-Finnish (FIN) AF: 0.708 AC: 7461 AN: 10544

Middle Eastern (MID) AF: 0.631 AC: 183 AN: 290

European-Non Finnish (NFE) AF: 0.698 AC: 47437 AN: 67950

Other (OTH) AF: 0.626 AC: 1317 AN: 2104

Alfa AF: 0.665 Hom.: 151276

Bravo AF: 0.614

TwinsUK AF: 0.709 AC: 2630

ALSPAC AF: 0.714 AC: 2751

ESP6500AA AF: 0.580 AC: 2557

ESP6500EA AF: 0.702 AC: 6036

ExAC AF: 0.624 AC: 75760

Asia WGS AF: 0.563 AC: 1958 AN: 3478

EpiCase AF: 0.682

EpiControl AF: 0.681

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Pontocerebellar hypoplasia type 2A (1)
-	-	1	Pontocerebellar hypoplasia type 4 (1)
-	-	1	Pontocerebellar hypoplasia type 5 (1)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0000049	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.44
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.10
Sift	Benign	0.49	T
Sift4G	Benign	0.14	T
Polyphen		0.70	P
Vest4		0.027
MPC		0.26
ClinPred		0.013	T
GERP RS		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.018
gMVP		0.25
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8064529; hg19: chr17-73519413; COSMIC: COSV51350086; COSMIC: COSV51350086;