19-54190921-G-C

Variant names:

• chr19-54190921-G-C
• rs145947907
• ENST00000396383.5:c.-121G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001282332.2(TSEN34):​c.-121G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000882 in 1,050,108 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (7 hom., cov: 34)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: TSEN34 NM_001282332.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.919
• Publications: 0 publications found

Genes affected

TSEN34 (HGNC:15506): (tRNA splicing endonuclease subunit 34) This gene encodes a catalytic subunit of the tRNA splicing endonuclease, which catalyzes the removal of introns from precursor tRNAs. The endonuclease complex is also associated with a pre-mRNA 3-prime end processing factor. A mutation in this gene results in the neurological disorder pontocerebellar hypoplasia type 2. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Oct 2009]

TSEN34 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 2C

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-54190921-G-C is Benign according to our data. Variant chr19-54190921-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1190073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282332.2. 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
	TSEN34	NM_001282332.2		c.-121G>C		5_prime_UTR	Exon 1 of 5	NP_001269261.1	Q9BSV6
	TSEN34	NM_001282333.2		c.-4-440G>C		intron	N/A	NP_001269262.2	A0A590UJW4
	TSEN34	NM_001386740.1		c.-4-440G>C		intron	N/A	NP_001373669.1	Q9BSV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	ENST00000396383.5	TSL:1	c.-121G>C		5_prime_UTR	Exon 1 of 5	ENSP00000379667.1	Q9BSV6
	TSEN34	ENST00000302937.8	TSL:1	c.-4-440G>C		intron	N/A	ENSP00000305524.4	Q9BSV6
	TSEN34	ENST00000862765.1		c.-125G>C		5_prime_UTR	Exon 1 of 5	ENSP00000532824.1

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 684 AN: 152258 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.000272 AC: 244 AN: 897732 Hom.: 1 Cov.: 31 AF XY: 0.000254 AC XY: 106 AN XY: 417382

African (AFR) AF: 0.0114 AC: 199 AN: 17464

American (AMR) AF: 0.00289 AC: 8 AN: 2766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7200

East Asian (EAS) AF: 0.00 AC: 0 AN: 6830

South Asian (SAS) AF: 0.00 AC: 0 AN: 21966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3720

Middle Eastern (MID) AF: 0.00207 AC: 4 AN: 1930

European-Non Finnish (NFE) AF: 0.00000249 AC: 2 AN: 804438

Other (OTH) AF: 0.000987 AC: 31 AN: 31418

GnomAD4 genome AF: 0.00448 AC: 682 AN: 152376 Hom.: 7 Cov.: 34 AF XY: 0.00397 AC XY: 296 AN XY: 74512

African (AFR) AF: 0.0146 AC: 606 AN: 41600

American (AMR) AF: 0.00425 AC: 65 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00573

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, autosomal recessive 57 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.7
DANN	Benign	0.60
PhyloP100		0.92
PromoterAI		0.15	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs145947907; hg19: chr19-54694772;