16-75647925-A-C

Position:

• chr16-75647925-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000300086.5(TERF2IP):​c.43A>C​(p.Thr15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T15I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TERF2IP ENST00000300086.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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]

KARS1 (HGNC:6215): (lysyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27000636).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERF2IP	NM_018975.4	c.43A>C	p.Thr15Pro	missense_variant	1/3	ENST00000300086.5	NP_061848.2
TERF2IP	XM_047434216.1	c.43A>C	p.Thr15Pro	missense_variant	1/2		XP_047290172.1
TERF2IP	NR_144545.2	n.153A>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERF2IP	ENST00000300086.5	c.43A>C	p.Thr15Pro	missense_variant	1/3	1	NM_018975.4	ENSP00000300086	P1
KARS1	ENST00000566560.5	n.176+543T>G		intron_variant, non_coding_transcript_variant		1
TERF2IP	ENST00000653858.1	c.43A>C	p.Thr15Pro	missense_variant	1/4			ENSP00000499565

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2022

The p.T15P variant (also known as c.43A>C), located in coding exon 1 of the TERF2IP gene, results from an A to C substitution at nucleotide position 43. The threonine at codon 15 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.93	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.017	D
Polyphen		0.84	P
Vest4		0.27
MutPred		0.22		Gain of catalytic residue at P14 (P = 0.0119);
MVP		0.66
MPC		1.1
ClinPred		0.93	D
GERP RS		4.6
Varity_R		0.41
gMVP		0.41

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: rs1597182880; hg19: chr16-75681823;