14-20368542-G-C

Variant names:

• chr14-20368542-G-C
• rs200480632
• NM_007110.5:c.7779C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007110.5(TEP1):​c.7779C>G​(p.Cys2593Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C2593C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TEP1 NM_007110.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0850
• Publications: 0 publications found

Genes affected

TEP1 (HGNC:11726): (telomerase associated protein 1) This gene product is a component of the ribonucleoprotein complex responsible for telomerase activity which catalyzes the addition of new telomeres on the chromosome ends. The telomerase-associated proteins are conserved from ciliates to humans. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

TEP1 Gene-Disease associations (from GenCC):

• cerebral palsy

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007110.5. 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
	TEP1	NM_007110.5	MANE Select	c.7779C>G	p.Cys2593Trp	missense	Exon 55 of 55	NP_009041.2
	TEP1	NM_001319035.2		c.7455C>G	p.Cys2485Trp	missense	Exon 53 of 53	NP_001305964.1	G3V5X7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEP1	ENST00000262715.10	TSL:1 MANE Select	c.7779C>G	p.Cys2593Trp	missense	Exon 55 of 55	ENSP00000262715.5	Q99973-1
	TEP1	ENST00000556935.5	TSL:1	c.7455C>G	p.Cys2485Trp	missense	Exon 53 of 53	ENSP00000452574.1	G3V5X7
	TEP1	ENST00000553365.5	TSL:1	n.*143C>G		non_coding_transcript_exon	Exon 8 of 9	ENSP00000450475.1	H0YIY9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.085
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.73		Loss of methylation at R2592 (P = 0.0763)
MVP		0.34
MPC		0.63
ClinPred		1.0	D
GERP RS		-2.2
Varity_R		0.82
gMVP		0.58
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs200480632; hg19: chr14-20836701;