14-20369351-C-G

Variant names:

• chr14-20369351-C-G
• rs190503710
• NM_007110.5:c.7649G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007110.5(TEP1):​c.7649G>C​(p.Arg2550Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2550H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TEP1 NM_007110.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.438
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21191439).

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.7649G>C	p.Arg2550Pro	missense	Exon 53 of 55	NP_009041.2
	TEP1	NM_001319035.2		c.7325G>C	p.Arg2442Pro	missense	Exon 51 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.7649G>C	p.Arg2550Pro	missense	Exon 53 of 55	ENSP00000262715.5	Q99973-1
	TEP1	ENST00000556935.5	TSL:1	c.7325G>C	p.Arg2442Pro	missense	Exon 51 of 53	ENSP00000452574.1	G3V5X7
	TEP1	ENST00000553365.5	TSL:1	n.*13G>C		non_coding_transcript_exon	Exon 6 of 9	ENSP00000450475.1	H0YIY9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251426 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.82
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.44
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Benign	0.38	T
Sift4G	Benign	0.31	T
Polyphen		0.93	P
Vest4		0.41
MutPred		0.53		Loss of MoRF binding (P = 0.0073)
MVP		0.55
MPC		0.52
ClinPred		0.39	T
GERP RS		1.6
Varity_R		0.30
gMVP		0.15
Mutation Taster		=94/6	polymorphism

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: rs190503710; hg19: chr14-20837510;