17-75516569-C-G

Variant names:

• chr17-75516569-C-G
• rs1403122330
• NM_207346.3:c.9C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_207346.3(TSEN54):​c.9C>G​(p.Pro3Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 981,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P3P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSEN54 NM_207346.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.940
• 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 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 17-75516569-C-G is Benign according to our data. Variant chr17-75516569-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2895050.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.94 with no splicing effect.

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.9C>G	p.Pro3Pro	synonymous	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.9C>G	p.Pro3Pro	synonymous	Exon 1 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.9C>G	p.Pro3Pro	synonymous	Exon 1 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.9C>G	p.Pro3Pro	synonymous	Exon 1 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.0000286 AC: 4 AN: 139646 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000706

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000318

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 96 AF XY: 0.00

Gnomad NFE exome AF: 0.00

GnomAD4 exome AF: 0.0000265 AC: 26 AN: 981466 Hom.: 0 Cov.: 28 AF XY: 0.0000346 AC XY: 16 AN XY: 462132

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18944

American (AMR) AF: 0.00 AC: 0 AN: 5418

Ashkenazi Jewish (ASJ) AF: 0.0000950 AC: 1 AN: 10522

East Asian (EAS) AF: 0.00 AC: 0 AN: 17688

South Asian (SAS) AF: 0.00 AC: 0 AN: 18466

European-Finnish (FIN) AF: 0.0000612 AC: 1 AN: 16340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2404

European-Non Finnish (NFE) AF: 0.0000246 AC: 21 AN: 854728

Other (OTH) AF: 0.0000812 AC: 3 AN: 36956

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000245987), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000286 AC: 4 AN: 139646 Hom.: 0 Cov.: 33 AF XY: 0.0000587 AC XY: 4 AN XY: 68152

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 37746

American (AMR) AF: 0.0000706 AC: 1 AN: 14168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3248

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4394

European-Finnish (FIN) AF: 0.000111 AC: 1 AN: 9038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000318 AC: 2 AN: 62860

Other (OTH) AF: 0.00 AC: 0 AN: 1904

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0339446), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000845 Hom.: 0

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.4
DANN	Benign	0.72
PhyloP100		-0.94
PromoterAI		0.022	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1403122330; hg19: chr17-73512650; COSMIC: COSV105892128; COSMIC: COSV105892128;