rs2289145

Variant names:

• chr19-54193391-G-A
• rs2289145
• NM_001077446.4:c.*29G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-54193391-G-A
• chr19-54193391-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001077446.4(TSEN34):​c.*29G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,613,706 control chromosomes in the GnomAD database, including 737 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (117 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (620 hom.)
• Consequence: TSEN34 NM_001077446.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.113
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-54193391-G-A is Benign according to our data. Variant chr19-54193391-G-A is described in ClinVar as Benign. ClinVar VariationId is 261679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 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.*29G>A		3_prime_UTR	Exon 4 of 4	NP_001070914.1	Q9BSV6
	TSEN34	NM_001282332.2		c.*29G>A		3_prime_UTR	Exon 5 of 5	NP_001269261.1	Q9BSV6
	TSEN34	NM_001386740.1		c.*29G>A		3_prime_UTR	Exon 5 of 5	NP_001373669.1	Q9BSV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	ENST00000396388.3	TSL:1 MANE Select	c.*29G>A		3_prime_UTR	Exon 4 of 4	ENSP00000379671.2	Q9BSV6
	TSEN34	ENST00000302937.8	TSL:1	c.*29G>A		3_prime_UTR	Exon 5 of 5	ENSP00000305524.4	Q9BSV6
	TSEN34	ENST00000396383.5	TSL:1	c.*29G>A		3_prime_UTR	Exon 5 of 5	ENSP00000379667.1	Q9BSV6

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3625 AN: 152166 Hom.: 117 Cov.: 32

Gnomad AFR AF: 0.0509

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0211 AC: 5234 AN: 248252 AF XY: 0.0178

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.0299

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.135

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.00856 AC: 12509 AN: 1461422 Hom.: 620 Cov.: 33 AF XY: 0.00811 AC XY: 5895 AN XY: 726970

African (AFR) AF: 0.0519 AC: 1736 AN: 33450

American (AMR) AF: 0.0287 AC: 1282 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26116

East Asian (EAS) AF: 0.151 AC: 6001 AN: 39672

South Asian (SAS) AF: 0.00347 AC: 299 AN: 86208

European-Finnish (FIN) AF: 0.0292 AC: 1561 AN: 53382

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5752

European-Non Finnish (NFE) AF: 0.000623 AC: 693 AN: 1111796

Other (OTH) AF: 0.0141 AC: 849 AN: 60376

GnomAD4 genome AF: 0.0239 AC: 3638 AN: 152284 Hom.: 117 Cov.: 32 AF XY: 0.0250 AC XY: 1863 AN XY: 74460

African (AFR) AF: 0.0510 AC: 2119 AN: 41560

American (AMR) AF: 0.0183 AC: 280 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.132 AC: 683 AN: 5180

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4830

European-Finnish (FIN) AF: 0.0302 AC: 320 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68016

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.00929 Hom.: 70

Bravo AF: 0.0258

Asia WGS AF: 0.0700 AC: 243 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.52
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs2289145; hg19: chr19-54697246; COSMIC: COSV55475902; COSMIC: COSV55475902;