NM_001077446.4:c.795T>C

Variant names:

• chr19-54193224-T-C
• rs7595
• NM_001077446.4:c.795T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001077446.4(TSEN34):​c.795T>C​(p.Pro265Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,613,742 control chromosomes in the GnomAD database, including 34,844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (3517 hom., cov: 31)
  • Exomes 𝑓: 0.20 (31327 hom.)
• Consequence: TSEN34 NM_001077446.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.89
• Publications: 36 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-54193224-T-C is Benign according to our data. Variant chr19-54193224-T-C is described in ClinVar as Benign. ClinVar VariationId is 1637899.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077446.4. 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_001077446.4	MANE Select	c.795T>C	p.Pro265Pro	synonymous	Exon 4 of 4	NP_001070914.1	Q9BSV6
	TSEN34	NM_001282333.2		c.795T>C	p.Pro265Pro	synonymous	Exon 5 of 6	NP_001269262.2	A0A590UJW4
	TSEN34	NM_001282332.2		c.795T>C	p.Pro265Pro	synonymous	Exon 5 of 5	NP_001269261.1	Q9BSV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	ENST00000396388.3	TSL:1 MANE Select	c.795T>C	p.Pro265Pro	synonymous	Exon 4 of 4	ENSP00000379671.2	Q9BSV6
	TSEN34	ENST00000302937.8	TSL:1	c.795T>C	p.Pro265Pro	synonymous	Exon 5 of 5	ENSP00000305524.4	Q9BSV6
	TSEN34	ENST00000396383.5	TSL:1	c.795T>C	p.Pro265Pro	synonymous	Exon 5 of 5	ENSP00000379667.1	Q9BSV6

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30845 AN: 151794 Hom.: 3512 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.215

GnomAD4 exome AF: 0.196 AC: 287072 AN: 1461828 Hom.: 31327 Cov.: 34 AF XY: 0.196 AC XY: 142410 AN XY: 727214

African (AFR) AF: 0.152 AC: 5076 AN: 33480

American (AMR) AF: 0.377 AC: 16850 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 4985 AN: 26136

East Asian (EAS) AF: 0.468 AC: 18593 AN: 39700

South Asian (SAS) AF: 0.208 AC: 17931 AN: 86252

European-Finnish (FIN) AF: 0.183 AC: 9748 AN: 53412

Middle Eastern (MID) AF: 0.161 AC: 924 AN: 5726

European-Non Finnish (NFE) AF: 0.180 AC: 200447 AN: 1112010

Other (OTH) AF: 0.207 AC: 12518 AN: 60392

GnomAD4 genome AF: 0.203 AC: 30866 AN: 151914 Hom.: 3517 Cov.: 31 AF XY: 0.207 AC XY: 15387 AN XY: 74228

African (AFR) AF: 0.159 AC: 6583 AN: 41464

American (AMR) AF: 0.309 AC: 4705 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 695 AN: 3470

East Asian (EAS) AF: 0.505 AC: 2603 AN: 5154

South Asian (SAS) AF: 0.208 AC: 999 AN: 4810

European-Finnish (FIN) AF: 0.187 AC: 1974 AN: 10550

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12585 AN: 67936

Other (OTH) AF: 0.217 AC: 456 AN: 2100

Alfa AF: 0.194 Hom.: 9729

Bravo AF: 0.211

ClinVar

ClinVar submissions

Significance: 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	-0.81
CADD	Benign	0.10
PhyloP100		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

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

Other links and lift over

dbSNP: rs7595; hg19: chr19-54697079;