NM_207346.3:c.222-18C>T

Variant names:

• chr17-75516991-C-T
• rs113255333
• NM_207346.3:c.222-18C>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.222-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0281 in 1,570,044 control chromosomes in the GnomAD database, including 777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (67 hom., cov: 33)
  • Exomes 𝑓: 0.029 (710 hom.)
• Consequence: TSEN54 NM_207346.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.392
• 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 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-75516991-C-T is Benign according to our data. Variant chr17-75516991-C-T is described in ClinVar as Benign. ClinVar VariationId is 263291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0231 (3517/152308) while in subpopulation SAS AF = 0.0396 (191/4826). AF 95% confidence interval is 0.035. There are 67 homozygotes in GnomAd4. There are 1705 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 67 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	NM_207346.3	MANE Select	c.222-18C>T		intron	N/A	NP_997229.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	ENST00000333213.11	TSL:1 MANE Select	c.222-18C>T		intron	N/A	ENSP00000327487.6
	TSEN54	ENST00000680999.1		c.222-18C>T		intron	N/A	ENSP00000504984.1
	TSEN54	ENST00000915433.1		c.222-18C>T		intron	N/A	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3517 AN: 152190 Hom.: 67 Cov.: 33

Gnomad AFR AF: 0.00548

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0398

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0318

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0273 AC: 4871 AN: 178474 AF XY: 0.0288

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0564

Gnomad EAS exome AF: 0.000148

Gnomad FIN exome AF: 0.0335

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0286 AC: 40552 AN: 1417736 Hom.: 710 Cov.: 54 AF XY: 0.0292 AC XY: 20482 AN XY: 701256

African (AFR) AF: 0.00395 AC: 128 AN: 32432

American (AMR) AF: 0.0154 AC: 595 AN: 38522

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 1352 AN: 25368

East Asian (EAS) AF: 0.0000537 AC: 2 AN: 37254

South Asian (SAS) AF: 0.0373 AC: 3015 AN: 80796

European-Finnish (FIN) AF: 0.0322 AC: 1570 AN: 48722

Middle Eastern (MID) AF: 0.0517 AC: 292 AN: 5644

European-Non Finnish (NFE) AF: 0.0293 AC: 31960 AN: 1090326

Other (OTH) AF: 0.0279 AC: 1638 AN: 58672

GnomAD4 genome AF: 0.0231 AC: 3517 AN: 152308 Hom.: 67 Cov.: 33 AF XY: 0.0229 AC XY: 1705 AN XY: 74470

African (AFR) AF: 0.00546 AC: 227 AN: 41582

American (AMR) AF: 0.0219 AC: 335 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0521 AC: 181 AN: 3472

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

South Asian (SAS) AF: 0.0396 AC: 191 AN: 4826

European-Finnish (FIN) AF: 0.0333 AC: 354 AN: 10620

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0318 AC: 2161 AN: 68010

Other (OTH) AF: 0.0237 AC: 50 AN: 2114

Alfa AF: 0.0325 Hom.: 24

Bravo AF: 0.0210

Asia WGS AF: 0.0180 AC: 65 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.6
DANN	Benign	0.90
PhyloP100		-0.39
PromoterAI		-0.028	Neutral
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: rs113255333; hg19: chr17-73513072; COSMIC: COSV58689953; COSMIC: COSV58689953;