NM_207346.3:c.333C>G

Variant names:

• chr17-75517208-C-G
• rs6501818
• NM_207346.3:c.333C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_207346.3(TSEN54):​c.333C>G​(p.Arg111Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,605,396 control chromosomes in the GnomAD database, including 17,701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3394 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14307 hom.)
• Consequence: TSEN54 NM_207346.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.683
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 17-75517208-C-G is Benign according to our data. Variant chr17-75517208-C-G is described in ClinVar as Benign. ClinVar VariationId is 137756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.683 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 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.333C>G	p.Arg111Arg	synonymous	Exon 4 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.333C>G	p.Arg111Arg	synonymous	Exon 4 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.333C>G	p.Arg111Arg	synonymous	Exon 4 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.333C>G	p.Arg111Arg	synonymous	Exon 4 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28132 AN: 152050 Hom.: 3384 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0205

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.126 AC: 29464 AN: 233248 AF XY: 0.124

Gnomad AFR exome AF: 0.331

Gnomad AMR exome AF: 0.0835

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0173

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.134 AC: 194522 AN: 1453228 Hom.: 14307 Cov.: 40 AF XY: 0.132 AC XY: 95593 AN XY: 722030

African (AFR) AF: 0.349 AC: 11606 AN: 33222

American (AMR) AF: 0.0871 AC: 3814 AN: 43770

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 4283 AN: 25922

East Asian (EAS) AF: 0.0179 AC: 705 AN: 39454

South Asian (SAS) AF: 0.0986 AC: 8363 AN: 84810

European-Finnish (FIN) AF: 0.114 AC: 5959 AN: 52290

Middle Eastern (MID) AF: 0.157 AC: 894 AN: 5692

European-Non Finnish (NFE) AF: 0.136 AC: 150703 AN: 1108028

Other (OTH) AF: 0.136 AC: 8195 AN: 60040

GnomAD4 genome AF: 0.185 AC: 28179 AN: 152168 Hom.: 3394 Cov.: 32 AF XY: 0.181 AC XY: 13497 AN XY: 74398

African (AFR) AF: 0.337 AC: 13967 AN: 41486

American (AMR) AF: 0.133 AC: 2041 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3468

East Asian (EAS) AF: 0.0201 AC: 104 AN: 5170

South Asian (SAS) AF: 0.101 AC: 489 AN: 4826

European-Finnish (FIN) AF: 0.109 AC: 1157 AN: 10608

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9402 AN: 68002

Other (OTH) AF: 0.178 AC: 377 AN: 2116

Alfa AF: 0.156 Hom.: 701

Bravo AF: 0.192

Asia WGS AF: 0.0890 AC: 312 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.4
DANN	Benign	0.78
PhyloP100		-0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs6501818; hg19: chr17-73513289; COSMIC: COSV108137747; COSMIC: COSV108137747;