14-20404722-G-T

Position:

• chr14-20404722-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007110.5(TEP1):​c.921C>A​(p.Asn307Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,613,300 control chromosomes in the GnomAD database, including 54,837 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.31 (8169 hom., cov: 32)
  • Exomes 𝑓: 0.25 (46668 hom.)
• Consequence: TEP1 NM_007110.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00100

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.589238E-5).
• BP6: Variant 14-20404722-G-T is Benign according to our data. Variant chr14-20404722-G-T is described in ClinVar as [Benign]. Clinvar id is 1232904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TEP1	NM_007110.5	c.921C>A	p.Asn307Lys	missense_variant	5/55	ENST00000262715.10	NP_009041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TEP1	ENST00000262715.10	c.921C>A	p.Asn307Lys	missense_variant	5/55	1	NM_007110.5	ENSP00000262715.5
TEP1	ENST00000556935.5	c.870+729C>A		intron_variant		1		ENSP00000452574.1
TEP1	ENST00000555727.5	n.921C>A		non_coding_transcript_exon_variant	5/54	1		ENSP00000451634.1

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46892 AN: 152012 Hom.: 8145 Cov.: 32

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.282

GnomAD3 exomes AF: 0.286 AC: 71713 AN: 250698 Hom.: 11371 AF XY: 0.279 AC XY: 37858 AN XY: 135556

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.351

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.441

Gnomad SAS exome AF: 0.335

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.245 AC: 358282 AN: 1461170 Hom.: 46668 Cov.: 33 AF XY: 0.245 AC XY: 178122 AN XY: 726888

Gnomad4 AFR exome AF: 0.480

Gnomad4 AMR exome AF: 0.343

Gnomad4 ASJ exome AF: 0.274

Gnomad4 EAS exome AF: 0.383

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.266

GnomAD4 genome AF: 0.309 AC: 46977 AN: 152130 Hom.: 8169 Cov.: 32 AF XY: 0.309 AC XY: 23007 AN XY: 74362

Gnomad4 AFR AF: 0.466

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.225

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.283

Alfa AF: 0.240 Hom.: 11546

Bravo AF: 0.320

TwinsUK AF: 0.221 AC: 821

ALSPAC AF: 0.210 AC: 811

ESP6500AA AF: 0.451 AC: 1989

ESP6500EA AF: 0.217 AC: 1865

ExAC AF: 0.286 AC: 34693

Asia WGS AF: 0.395 AC: 1374 AN: 3478

EpiCase AF: 0.218

EpiControl AF: 0.221

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 23907815) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.7
DANN	Benign	0.94
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.053	T
MetaRNN	Benign	0.000096	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.3	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.74	N
REVEL	Benign	0.014
Sift	Benign	0.30	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.065
MutPred		0.44		Gain of MoRF binding (P = 0.0353);
MPC		0.13
ClinPred		0.0056	T
GERP RS		-0.96
Varity_R		0.030
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1760898; hg19: chr14-20872881; COSMIC: COSV52990468; COSMIC: COSV52990468;