chr19-54191191-G-C

Variant names:

• chr19-54191191-G-C
• rs566932562
• ENST00000302937.8:c.-4-170G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001282333.2(TSEN34):​c.-4-170G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,387,238 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (7 hom.)
• Consequence: TSEN34 NM_001282333.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.42
• 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: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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=-0.7).
• BP6: Variant 19-54191191-G-C is Benign according to our data. Variant chr19-54191191-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1194740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00637 (970/152214) while in subpopulation AFR AF = 0.0213 (887/41552). AF 95% confidence interval is 0.0202. There are 16 homozygotes in GnomAd4. There are 481 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282333.2. 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_001282333.2		c.-4-170G>C		intron	N/A	NP_001269262.2	A0A590UJW4
	TSEN34	NM_001282332.2		c.-5+154G>C		intron	N/A	NP_001269261.1	Q9BSV6
	TSEN34	NM_001386740.1		c.-4-170G>C		intron	N/A	NP_001373669.1	Q9BSV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	ENST00000302937.8	TSL:1	c.-4-170G>C		intron	N/A	ENSP00000305524.4	Q9BSV6
	TSEN34	ENST00000396383.5	TSL:1	c.-5+154G>C		intron	N/A	ENSP00000379667.1	Q9BSV6
	TSEN34	ENST00000667261.1		c.-4-170G>C		intron	N/A	ENSP00000499595.1	A0A590UJW4

Frequencies

GnomAD3 genomes AF: 0.00636 AC: 968 AN: 152098 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.000572 AC: 706 AN: 1235024 Hom.: 7 Cov.: 33 AF XY: 0.000558 AC XY: 334 AN XY: 599018

African (AFR) AF: 0.0231 AC: 542 AN: 23462

American (AMR) AF: 0.00169 AC: 24 AN: 14226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16842

East Asian (EAS) AF: 0.00 AC: 0 AN: 29574

South Asian (SAS) AF: 0.000107 AC: 6 AN: 55940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31184

Middle Eastern (MID) AF: 0.000584 AC: 2 AN: 3426

European-Non Finnish (NFE) AF: 0.0000396 AC: 40 AN: 1009676

Other (OTH) AF: 0.00181 AC: 92 AN: 50694

GnomAD4 genome AF: 0.00637 AC: 970 AN: 152214 Hom.: 16 Cov.: 33 AF XY: 0.00646 AC XY: 481 AN XY: 74422

African (AFR) AF: 0.0213 AC: 887 AN: 41552

American (AMR) AF: 0.00379 AC: 58 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0138 AC: 4 AN: 290

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67978

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00122 Hom.: 2

Bravo AF: 0.00711

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.77
PhyloP100		2.4
PromoterAI		0.29	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: rs566932562; hg19: chr19-54695042;