14-20373548-C-T

Variant names:

• chr14-20373548-C-T
• rs1713449
• NM_007110.5:c.6640G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007110.5(TEP1):​c.6640G>A​(p.Val2214Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,613,844 control chromosomes in the GnomAD database, including 44,660 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (7019 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37641 hom.)
• Consequence: TEP1 NM_007110.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011783242).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEP1	NM_007110.5	c.6640G>A	p.Val2214Ile	missense_variant	Exon 46 of 55	ENST00000262715.10	NP_009041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEP1	ENST00000262715.10	c.6640G>A	p.Val2214Ile	missense_variant	Exon 46 of 55	1	NM_007110.5	ENSP00000262715.5

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43946 AN: 151940 Hom.: 7015 Cov.: 32

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.294

GnomAD3 exomes AF: 0.263 AC: 66067 AN: 251304 Hom.: 9529 AF XY: 0.254 AC XY: 34549 AN XY: 135838

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.295

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.221 AC: 323285 AN: 1461786 Hom.: 37641 Cov.: 36 AF XY: 0.220 AC XY: 160238 AN XY: 727192

Gnomad4 AFR exome AF: 0.422

Gnomad4 AMR exome AF: 0.375

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.247

Gnomad4 SAS exome AF: 0.233

Gnomad4 FIN exome AF: 0.251

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.289 AC: 43989 AN: 152058 Hom.: 7019 Cov.: 32 AF XY: 0.292 AC XY: 21728 AN XY: 74348

Gnomad4 AFR AF: 0.415

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.297

Alfa AF: 0.232 Hom.: 9336

Bravo AF: 0.302

TwinsUK AF: 0.204 AC: 756

ALSPAC AF: 0.204 AC: 788

ESP6500AA AF: 0.410 AC: 1806

ESP6500EA AF: 0.205 AC: 1767

ExAC AF: 0.258 AC: 31337

Asia WGS AF: 0.314 AC: 1089 AN: 3478

EpiCase AF: 0.224

EpiControl AF: 0.226

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.073	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.052
Sift	Benign	0.20	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0010	B;B
Vest4		0.10
MPC		0.088
ClinPred		0.0025	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs1713449; hg19: chr14-20841707; COSMIC: COSV52989720; COSMIC: COSV52989720;