rs251796

Variant names:

• chr16-69361531-A-G
• rs251796
• NM_005652.5:c.1341-42T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 38 publications found

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

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005652.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERF2	NM_005652.5	MANE Select	c.1341-42T>C		intron	N/A	NP_005643.2	Q15554-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERF2	ENST00000254942.8	TSL:1 MANE Select	c.1341-42T>C		intron	N/A	ENSP00000254942.3	Q15554-3
	TERF2	ENST00000903039.1		c.1341-42T>C		intron	N/A	ENSP00000573098.1
	TERF2	ENST00000966429.1		c.1338-42T>C		intron	N/A	ENSP00000636488.1

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

GnomAD2 exomes AF: 0.312 AC: 77990 AN: 250350 AF XY: 0.314

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 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

African (AFR) AF: 0.0556 AC: 1597 AN: 28728

American (AMR) AF: 0.388 AC: 17199 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7226 AN: 24588

East Asian (EAS) AF: 0.358 AC: 13819 AN: 38624

South Asian (SAS) AF: 0.318 AC: 25954 AN: 81612

European-Finnish (FIN) AF: 0.380 AC: 20245 AN: 53236

Middle Eastern (MID) AF: 0.301 AC: 1591 AN: 5294

European-Non Finnish (NFE) AF: 0.301 AC: 270545 AN: 900108

Other (OTH) AF: 0.292 AC: 15347 AN: 52646

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

African (AFR) AF: 0.0609 AC: 2519 AN: 41368

American (AMR) AF: 0.315 AC: 4810 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1023 AN: 3468

East Asian (EAS) AF: 0.345 AC: 1770 AN: 5130

South Asian (SAS) AF: 0.310 AC: 1490 AN: 4812

European-Finnish (FIN) AF: 0.395 AC: 4147 AN: 10486

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20359 AN: 67868

Other (OTH) AF: 0.254 AC: 534 AN: 2106

Alfa AF: 0.288 Hom.: 15197

Bravo AF: 0.235

Asia WGS AF: 0.258 AC: 895 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.1
DANN	Benign	0.65
PhyloP100		1.0
BranchPoint Hunter		2.0
PromoterAI		0.010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs251796; hg19: chr16-69395434;