rs879253779

Variant names:

• chr1-184072258-A-G
• rs879253779
• NM_052965.4:c.455A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_052965.4(TSEN15):​c.455A>G​(p.Tyr152Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSEN15 NM_052965.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.61
• Publications: 0 publications found

Genes affected

TSEN15 (HGNC:16791): (tRNA splicing endonuclease subunit 15) This gene encodes a subunit of the tRNA splicing endonuclease, which catalyzes the removal of introns from tRNA precursors. Alternative splicing results in multiple transcript variants. There is a pseudogene of this gene on chromosome 17. [provided by RefSeq, Jul 2014]

TSEN15 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, type 2F

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant 1-184072258-A-G is Pathogenic according to our data. Variant chr1-184072258-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 243000.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052965.4. 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
	TSEN15	NM_052965.4	MANE Select	c.455A>G	p.Tyr152Cys	missense	Exon 4 of 5	NP_443197.1	Q8WW01-1
	TSEN15	NM_001300764.2		c.455A>G	p.Tyr152Cys	missense	Exon 4 of 5	NP_001287693.1	A0A2U3TZM3
	TSEN15	NM_001363643.2		c.353+17395A>G		intron	N/A	NP_001350572.1	A0A2R8YDU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN15	ENST00000645668.2	MANE Select	c.455A>G	p.Tyr152Cys	missense	Exon 4 of 5	ENSP00000493902.2	Q8WW01-1
	TSEN15	ENST00000361641.6	TSL:1	c.455A>G	p.Tyr152Cys	missense	Exon 4 of 5	ENSP00000355299.2	A0A2U3TZM3
	TSEN15	ENST00000462677.3	TSL:1	n.*158A>G		non_coding_transcript_exon	Exon 5 of 6	ENSP00000432397.2	H0YCV5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460922 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726736

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111534

Other (OTH) AF: 0.00 AC: 0 AN: 60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pontocerebellar hypoplasia, type 2F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.73		Gain of methylation at K154 (P = 0.0632)
MVP		0.88
MPC		1.6
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.90
gMVP		0.77
Mutation Taster		=31/69	disease causing (ClinVar)

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: rs879253779; hg19: chr1-184041392; COSMIC: COSV62294612; COSMIC: COSV62294612;