rs4888444

Positions:

• chr16-75656381-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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

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

Verdict is Benign. Variant got -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 id is 1697661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75656381-A-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERF2IP	NM_018975.4	c.970A>G	p.Lys324Glu	missense_variant	3/3	ENST00000300086.5
TERF2IP	NR_144545.2	n.1210A>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERF2IP	ENST00000300086.5	c.970A>G	p.Lys324Glu	missense_variant	3/3	1	NM_018975.4	P1

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

GnomAD3 exomes AF: 0.0342 AC: 8587 AN: 251282 Hom.: 182 AF XY: 0.0374 AC XY: 5084 AN XY: 135854

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 SAS exome AF: 0.0495

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

Gnomad4 AFR exome AF: 0.00627

Gnomad4 AMR exome AF: 0.0203

Gnomad4 ASJ exome AF: 0.0593

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0497

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.0461

Gnomad4 OTH exome AF: 0.0399

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

Gnomad4 AFR AF: 0.00799

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.0686

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0460

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.0442

Gnomad4 OTH AF: 0.0288

Alfa AF: 0.0421 Hom.: 317

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.70	D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.19

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: rs4888444; hg19: chr16-75690279;