rs251796

Positions:

• chr16-69361531-A-G

Variant summary

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

The NM_005652.5(TERF2):​c.1341-42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,380,914 control chromosomes in the GnomAD database, including 64,761 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.24 (5633 hom., cov: 30)
  • Exomes 𝑓: 0.30 (59128 hom.)
• Consequence: TERF2 NM_005652.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.03

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 -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 2 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-69361531-A-G is Benign according to our data. Variant chr16-69361531-A-G is described in ClinVar as [Benign]. Clinvar id is 1227895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERF2	NM_005652.5	c.1341-42T>C		intron_variant		ENST00000254942.8	NP_005643.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERF2	ENST00000254942.8	c.1341-42T>C		intron_variant		1	NM_005652.5	ENSP00000254942	P1
TERF2	ENST00000567130.1	n.179-42T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37055 AN: 151582 Hom.: 5637 Cov.: 30

Gnomad AFR AF: 0.0610

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.258

GnomAD3 exomes AF: 0.312 AC: 77990 AN: 250350 Hom.: 12981 AF XY: 0.314 AC XY: 42461 AN XY: 135360

Gnomad AFR exome AF: 0.0569

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.343

Gnomad SAS exome AF: 0.318

Gnomad FIN exome AF: 0.383

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.304 AC: 373523 AN: 1229214 Hom.: 59128 Cov.: 17 AF XY: 0.304 AC XY: 189740 AN XY: 623184

Gnomad4 AFR exome AF: 0.0556

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.358

Gnomad4 SAS exome AF: 0.318

Gnomad4 FIN exome AF: 0.380

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.292

GnomAD4 genome AF: 0.244 AC: 37034 AN: 151700 Hom.: 5633 Cov.: 30 AF XY: 0.251 AC XY: 18567 AN XY: 74116

Gnomad4 AFR AF: 0.0609

Gnomad4 AMR AF: 0.315

Gnomad4 ASJ AF: 0.295

Gnomad4 EAS AF: 0.345

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.300

Gnomad4 OTH AF: 0.254

Alfa AF: 0.295 Hom.: 10805

Bravo AF: 0.235

Asia WGS AF: 0.258 AC: 895 AN: 3478

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	Jun 14, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.1
DANN	Benign	0.65
BranchPoint Hunter		2.0

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: rs251796; hg19: chr16-69395434;