rs4888444

Variant names:

• chr16-75656381-A-G
• rs4888444
• NM_018975.4:c.970A>G

Variant summary

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

The NM_018975.4(TERF2IP):​c.970A>G​(p.Lys324Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0411 in 1,614,148 control chromosomes in the GnomAD database, including 1,560 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K324T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.030 (91 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1469 hom.)
• Consequence: TERF2IP NM_018975.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.26
• Publications: 27 publications found

Genes affected

TERF2IP (HGNC:19246): (TERF2 interacting protein) Enables G-rich strand telomeric DNA binding activity and phosphatase binding activity. Involved in several processes, including positive regulation of NIK/NF-kappaB signaling; regulation of nucleobase-containing compound metabolic process; and regulation of protein modification process. Located in chromosome, telomeric region; cytosol; and nuclear body. Part of shelterin complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013928115).
• BP6: Variant 16-75656381-A-G is Benign according to our data. Variant chr16-75656381-A-G is described in ClinVar as Benign. ClinVar VariationId is 1697661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018975.4. 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
	TERF2IP	NM_018975.4	MANE Select	c.970A>G	p.Lys324Glu	missense	Exon 3 of 3	NP_061848.2
	TERF2IP	NR_144545.2		n.1210A>G		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERF2IP	ENST00000300086.5	TSL:1 MANE Select	c.970A>G	p.Lys324Glu	missense	Exon 3 of 3	ENSP00000300086.4	Q9NYB0
	TERF2IP	ENST00000912662.1		c.1135A>G	p.Lys379Glu	missense	Exon 4 of 4	ENSP00000582721.1
	TERF2IP	ENST00000898756.1		c.967A>G	p.Lys323Glu	missense	Exon 3 of 3	ENSP00000568815.1

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4539 AN: 152180 Hom.: 91 Cov.: 33

Gnomad AFR AF: 0.00801

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0466

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0442

Gnomad OTH AF: 0.0291

GnomAD2 exomes AF: 0.0342 AC: 8587 AN: 251282 AF XY: 0.0374

Gnomad AFR exome AF: 0.00695

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.0606

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0450

Gnomad OTH exome AF: 0.0412

GnomAD4 exome AF: 0.0423 AC: 61790 AN: 1461850 Hom.: 1469 Cov.: 32 AF XY: 0.0428 AC XY: 31106 AN XY: 727224

African (AFR) AF: 0.00627 AC: 210 AN: 33480

American (AMR) AF: 0.0203 AC: 908 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0593 AC: 1549 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0497 AC: 4287 AN: 86258

European-Finnish (FIN) AF: 0.0154 AC: 824 AN: 53420

Middle Eastern (MID) AF: 0.0650 AC: 375 AN: 5768

European-Non Finnish (NFE) AF: 0.0461 AC: 51218 AN: 1111972

Other (OTH) AF: 0.0399 AC: 2411 AN: 60392

GnomAD4 genome AF: 0.0298 AC: 4535 AN: 152298 Hom.: 91 Cov.: 33 AF XY: 0.0286 AC XY: 2129 AN XY: 74478

African (AFR) AF: 0.00799 AC: 332 AN: 41560

American (AMR) AF: 0.0271 AC: 415 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 238 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0460 AC: 222 AN: 4822

European-Finnish (FIN) AF: 0.0139 AC: 148 AN: 10624

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0442 AC: 3006 AN: 68018

Other (OTH) AF: 0.0288 AC: 61 AN: 2116

Alfa AF: 0.0403 Hom.: 567

Bravo AF: 0.0286

TwinsUK AF: 0.0467 AC: 173

ALSPAC AF: 0.0459 AC: 177

ESP6500AA AF: 0.00887 AC: 39

ESP6500EA AF: 0.0464 AC: 399

ExAC AF: 0.0351 AC: 4266

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0490

EpiControl AF: 0.0502

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Benign	0.75
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		2.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.084
Sift	Benign	0.83	T
Sift4G	Benign	1.0	T
Polyphen		0.0080	B
Vest4		0.041
MPC		0.033
ClinPred		0.015	T
GERP RS		4.6
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.19
Mutation Taster		=95/5	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: rs4888444; hg19: chr16-75690279; COSMIC: COSV107355006;