rs138719855

Variant names:

• chr17-75521696-G-A
• rs138719855
• NM_207346.3:c.624-9G>A

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.624-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,612,748 control chromosomes in the GnomAD database, including 453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (14 hom., cov: 32)
  • Exomes 𝑓: 0.022 (439 hom.)
• Consequence: TSEN54 NM_207346.3 intron
• Scores: Splicing: ADA: 0.00006446
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.10
• Publications: 0 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=-0.68).
• BP6: Variant 17-75521696-G-A is Benign according to our data. Variant chr17-75521696-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0145 (2208/152136) while in subpopulation NFE AF = 0.0242 (1644/67984). AF 95% confidence interval is 0.0232. There are 14 homozygotes in GnomAd4. There are 975 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.624-9G>A		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.624-9G>A		intron	N/A	ENSP00000327487.6
	TSEN54	ENST00000580013.6	TSL:4	n.818G>A		non_coding_transcript_exon	Exon 7 of 9
	TSEN54	ENST00000679370.1		n.1196G>A		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2208 AN: 152018 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00768

Gnomad FIN AF: 0.00604

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0242

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0134 AC: 3337 AN: 248392 AF XY: 0.0137

Gnomad AFR exome AF: 0.00404

Gnomad AMR exome AF: 0.00770

Gnomad ASJ exome AF: 0.00589

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00615

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0220 AC: 32114 AN: 1460612 Hom.: 439 Cov.: 30 AF XY: 0.0215 AC XY: 15647 AN XY: 726588

African (AFR) AF: 0.00466 AC: 156 AN: 33464

American (AMR) AF: 0.00812 AC: 363 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00509 AC: 133 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.00965 AC: 832 AN: 86246

European-Finnish (FIN) AF: 0.00662 AC: 348 AN: 52604

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5766

European-Non Finnish (NFE) AF: 0.0262 AC: 29116 AN: 1111662

Other (OTH) AF: 0.0183 AC: 1103 AN: 60356

GnomAD4 genome AF: 0.0145 AC: 2208 AN: 152136 Hom.: 14 Cov.: 32 AF XY: 0.0131 AC XY: 975 AN XY: 74368

African (AFR) AF: 0.00424 AC: 176 AN: 41492

American (AMR) AF: 0.0104 AC: 159 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

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

South Asian (SAS) AF: 0.00789 AC: 38 AN: 4814

European-Finnish (FIN) AF: 0.00604 AC: 64 AN: 10590

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0242 AC: 1644 AN: 67984

Other (OTH) AF: 0.0157 AC: 33 AN: 2108

Alfa AF: 0.0173 Hom.: 23

Bravo AF: 0.0153

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0214

EpiControl AF: 0.0199

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.8
DANN	Benign	0.77
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.070
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: rs138719855; hg19: chr17-73517777;