17-75522203-G-T

Variant names:

• chr17-75522203-G-T
• rs6501820
• NM_207346.3:c.1122G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_207346.3(TSEN54):​c.1122G>T​(p.Arg374Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R374R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TSEN54 NM_207346.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0780
• Publications: 19 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: 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=-0.59).
• BP7: Synonymous conserved (PhyloP=0.078 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	NM_207346.3	MANE Select	c.1122G>T	p.Arg374Arg	synonymous	Exon 8 of 11	NP_997229.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	ENST00000333213.11	TSL:1 MANE Select	c.1122G>T	p.Arg374Arg	synonymous	Exon 8 of 11	ENSP00000327487.6
	TSEN54	ENST00000680999.1		c.1122G>T	p.Arg374Arg	synonymous	Exon 8 of 11	ENSP00000504984.1
	TSEN54	ENST00000545228.3	TSL:5	c.1122G>T	p.Arg374Arg	synonymous	Exon 8 of 11	ENSP00000438169.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000638 AC: 1 AN: 156712 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397718 Hom.: 0 Cov.: 81 AF XY: 0.00 AC XY: 0 AN XY: 688672

African (AFR) AF: 0.00 AC: 0 AN: 31584

American (AMR) AF: 0.00 AC: 0 AN: 36434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25116

East Asian (EAS) AF: 0.00 AC: 0 AN: 35750

South Asian (SAS) AF: 0.00 AC: 0 AN: 79274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077854

Other (OTH) AF: 0.00 AC: 0 AN: 57906

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000204 Hom.: 19813

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.5
DANN	Benign	0.70
PhyloP100		0.078

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6501820; hg19: chr17-73518284;