rs8074291

Variant names:

• chr17-75517075-G-A
• rs8074291
• NM_207346.3:c.285+3G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_207346.3(TSEN54):​c.285+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,592,506 control chromosomes in the GnomAD database, including 17,672 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3402 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14270 hom.)
• Consequence: TSEN54 NM_207346.3 splice_region, intron
• Scores: Splicing: ADA: 0.001151
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.36
• Publications: 11 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 17-75517075-G-A is Benign according to our data. Variant chr17-75517075-G-A is described in ClinVar as Benign. ClinVar VariationId is 137755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.285+3G>A		splice_region intron	N/A	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.285+3G>A		splice_region intron	N/A	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.285+3G>A		splice_region intron	N/A	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.285+3G>A		splice_region intron	N/A	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28151 AN: 152100 Hom.: 3392 Cov.: 33

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0207

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.129 AC: 27006 AN: 209186 AF XY: 0.127

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.0874

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.0181

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.134 AC: 193417 AN: 1440288 Hom.: 14270 Cov.: 54 AF XY: 0.133 AC XY: 94938 AN XY: 714632

African (AFR) AF: 0.350 AC: 11576 AN: 33088

American (AMR) AF: 0.0900 AC: 3752 AN: 41706

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4264 AN: 25718

East Asian (EAS) AF: 0.0181 AC: 703 AN: 38758

South Asian (SAS) AF: 0.0989 AC: 8231 AN: 83232

European-Finnish (FIN) AF: 0.114 AC: 5740 AN: 50260

Middle Eastern (MID) AF: 0.157 AC: 898 AN: 5726

European-Non Finnish (NFE) AF: 0.136 AC: 150102 AN: 1102258

Other (OTH) AF: 0.137 AC: 8151 AN: 59542

GnomAD4 genome AF: 0.185 AC: 28198 AN: 152218 Hom.: 3402 Cov.: 33 AF XY: 0.181 AC XY: 13502 AN XY: 74418

African (AFR) AF: 0.337 AC: 13992 AN: 41522

American (AMR) AF: 0.133 AC: 2041 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 567 AN: 3472

East Asian (EAS) AF: 0.0203 AC: 105 AN: 5166

South Asian (SAS) AF: 0.101 AC: 490 AN: 4830

European-Finnish (FIN) AF: 0.108 AC: 1149 AN: 10604

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

European-Non Finnish (NFE) AF: 0.138 AC: 9401 AN: 68000

Other (OTH) AF: 0.178 AC: 377 AN: 2114

Alfa AF: 0.159 Hom.: 1058

Bravo AF: 0.192

Asia WGS AF: 0.0890 AC: 313 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	-0.36
CADD	Benign	21
DANN	Benign	0.95
PhyloP100		2.4
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.010
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: rs8074291; hg19: chr17-73513156; COSMIC: COSV58691261; COSMIC: COSV58691261;