14-20369542-G-C

Variant names:

• chr14-20369542-G-C
• rs938886
• NM_007110.5:c.7458C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007110.5(TEP1):​c.7458C>G​(p.Ile2486Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,613,600 control chromosomes in the GnomAD database, including 46,967 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7855 hom., cov: 31)
  • Exomes 𝑓: 0.22 (39112 hom.)
• Consequence: TEP1 NM_007110.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.591
• Publications: 42 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.7031045E-4).
• BP6: Variant 14-20369542-G-C is Benign according to our data. Variant chr14-20369542-G-C is described in ClinVar as Benign. ClinVar VariationId is 1232563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEP1	NM_007110.5	MANE Select	c.7458C>G	p.Ile2486Met	missense	Exon 53 of 55	NP_009041.2
	TEP1	NM_001319035.2		c.7134C>G	p.Ile2378Met	missense	Exon 51 of 53	NP_001305964.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEP1	ENST00000262715.10	TSL:1 MANE Select	c.7458C>G	p.Ile2486Met	missense	Exon 53 of 55	ENSP00000262715.5
	TEP1	ENST00000556935.5	TSL:1	c.7134C>G	p.Ile2378Met	missense	Exon 51 of 53	ENSP00000452574.1
	TEP1	ENST00000553365.5	TSL:1	n.575C>G		non_coding_transcript_exon	Exon 6 of 9	ENSP00000450475.1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 45945 AN: 151722 Hom.: 7849 Cov.: 31

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.301

GnomAD2 exomes AF: 0.267 AC: 67149 AN: 251386 AF XY: 0.258

Gnomad AFR exome AF: 0.458

Gnomad AMR exome AF: 0.379

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.295

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.225 AC: 328653 AN: 1461760 Hom.: 39112 Cov.: 35 AF XY: 0.224 AC XY: 162727 AN XY: 727192

African (AFR) AF: 0.461 AC: 15436 AN: 33480

American (AMR) AF: 0.379 AC: 16967 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6959 AN: 26134

East Asian (EAS) AF: 0.247 AC: 9802 AN: 39700

South Asian (SAS) AF: 0.235 AC: 20235 AN: 86252

European-Finnish (FIN) AF: 0.251 AC: 13399 AN: 53420

Middle Eastern (MID) AF: 0.311 AC: 1792 AN: 5768

European-Non Finnish (NFE) AF: 0.206 AC: 229410 AN: 1111908

Other (OTH) AF: 0.243 AC: 14653 AN: 60386

GnomAD4 genome AF: 0.303 AC: 45980 AN: 151840 Hom.: 7855 Cov.: 31 AF XY: 0.306 AC XY: 22700 AN XY: 74178

African (AFR) AF: 0.458 AC: 18938 AN: 41372

American (AMR) AF: 0.360 AC: 5478 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 912 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1520 AN: 5160

South Asian (SAS) AF: 0.240 AC: 1154 AN: 4804

European-Finnish (FIN) AF: 0.255 AC: 2691 AN: 10552

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14379 AN: 67948

Other (OTH) AF: 0.304 AC: 637 AN: 2098

Alfa AF: 0.214 Hom.: 2836

Bravo AF: 0.316

TwinsUK AF: 0.207 AC: 766

ALSPAC AF: 0.209 AC: 806

ESP6500AA AF: 0.437 AC: 1925

ESP6500EA AF: 0.207 AC: 1780

ExAC AF: 0.263 AC: 31913

Asia WGS AF: 0.314 AC: 1091 AN: 3478

EpiCase AF: 0.226

EpiControl AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19766477)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.14
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.00047	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.59
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.012
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.11
ClinPred		0.00059	T
GERP RS		2.8
Varity_R		0.025
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs938886; hg19: chr14-20837701; COSMIC: COSV52990531; COSMIC: COSV52990531;