17-75516563-GGAGCCC-GGAGCCCGAGCCC

Variant names:

• chr17-75516563-G-GGAGCCC
• rs904918193
• NM_207346.3:c.17_22dupAGCCCG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM4 BP6_Moderate

The NM_207346.3(TSEN54):​c.17_22dupAGCCCG​(p.Glu6_Pro7dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000008 in 1,124,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: TSEN54 NM_207346.3 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.417
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_207346.3.
• BP6: Variant 17-75516563-G-GGAGCCC is Benign according to our data. Variant chr17-75516563-G-GGAGCCC is described in ClinVar as Likely_benign. ClinVar VariationId is 2961742.Status of the report is criteria_provided_single_submitter, 1 stars.

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.17_22dupAGCCCG	p.Glu6_Pro7dup	disruptive_inframe_insertion	Exon 1 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.17_22dupAGCCCG	p.Glu6_Pro7dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.17_22dupAGCCCG	p.Glu6_Pro7dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.17_22dupAGCCCG	p.Glu6_Pro7dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.0000385 AC: 5 AN: 129752 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000866

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000757

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000171

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000402 AC: 4 AN: 994984 Hom.: 0 Cov.: 28 AF XY: 0.00000427 AC XY: 2 AN XY: 468318

African (AFR) AF: 0.00 AC: 0 AN: 19752

American (AMR) AF: 0.00 AC: 0 AN: 5514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10612

East Asian (EAS) AF: 0.0000581 AC: 1 AN: 17218

South Asian (SAS) AF: 0.0000532 AC: 1 AN: 18780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2448

European-Non Finnish (NFE) AF: 0.00000231 AC: 2 AN: 866802

Other (OTH) AF: 0.00 AC: 0 AN: 37464

GnomAD4 genome AF: 0.0000385 AC: 5 AN: 129752 Hom.: 0 Cov.: 33 AF XY: 0.0000474 AC XY: 3 AN XY: 63346

African (AFR) AF: 0.0000866 AC: 3 AN: 34638

American (AMR) AF: 0.0000757 AC: 1 AN: 13204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2994

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000171 AC: 1 AN: 58354

Other (OTH) AF: 0.00 AC: 0 AN: 1778

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=79/21	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs904918193; hg19: chr17-73512644;