rs13337258

chr16-69366892-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005652.5(TERF2):c.1255C>G(p.Leu419Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,218 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (10 hom.)
• Consequence: TERF2 NM_005652.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.54

Genes affected

TERF2 (HGNC:11729): (telomeric repeat binding factor 2) This gene encodes a telomere specific protein, TERF2, which is a component of the telomere nucleoprotein complex. This protein is present at telomeres in metaphase of the cell cycle, is a second negative regulator of telomere length and plays a key role in the protective activity of telomeres. While having similar telomere binding activity and domain organization, TERF2 differs from TERF1 in that its N terminus is basic rather than acidic. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045465827).
• BP6: Variant 16-69366892-G-C is Benign according to our data. Variant chr16-69366892-G-C is described in ClinVar as [Benign]. Clinvar id is 712847.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00647 (986/152366) while in subpopulation AFR AF= 0.0227 (942/41584). AF 95% confidence interval is 0.0215. There are 11 homozygotes in gnomad4. There are 463 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 982 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERF2	NM_005652.5	c.1255C>G	p.Leu419Val	missense_variant	7/10	ENST00000254942.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERF2	ENST00000254942.8	c.1255C>G	p.Leu419Val	missense_variant	7/10	1	NM_005652.5	P1
TERF2	ENST00000569584.6	c.577C>G	p.Leu193Val	missense_variant	4/4	2
TERF2	ENST00000567130.1	n.93C>G		non_coding_transcript_exon_variant	1/2	2
TERF2	ENST00000566750.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00645 AC: 982 AN: 152248 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00160 AC: 403 AN: 251306 Hom.: 4 AF XY: 0.00114 AC XY: 155 AN XY: 135854

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000687 AC: 1004 AN: 1461852 Hom.: 10 Cov.: 31 AF XY: 0.000611 AC XY: 444 AN XY: 727224

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00647 AC: 986 AN: 152366 Hom.: 11 Cov.: 32 AF XY: 0.00621 AC XY: 463 AN XY: 74522

Gnomad4 AFR AF: 0.0227

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00232 Hom.: 3

Bravo AF: 0.00728

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	16
Dann	Benign	0.068
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.30	T
REVEL	Benign	0.069
Sift4G	Benign	0.79	T
Vest4		0.069
MVP		0.73
ClinPred		0.053	T
GERP RS		5.1
Varity_R		0.047
gMVP		0.14

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: rs13337258; hg19: chr16-69400795; COSMIC: COSV99076952; COSMIC: COSV99076952;