14-24240642-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001099274.3(TINF2):c.838A>G(p.Lys280Glu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K280Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 3.58

Genes affected

TINF2 (HGNC:11824): (TERF1 interacting nuclear factor 2) This gene encodes one of the proteins of the shelterin, or telosome, complex which protects telomeres by allowing the cell to distinguish between telomeres and regions of DNA damage. The protein encoded by this gene is a critical part of shelterin; it interacts with the three DNA-binding proteins of the shelterin complex, and it is important for assembly of the complex. Mutations in this gene cause dyskeratosis congenita (DKC), an inherited bone marrow failure syndrome. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001099274.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 14-24240642-T-C is Pathogenic according to our data. Variant chr14-24240642-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 5624.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-24240642-T-C is described in UniProt as null. Variant chr14-24240642-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TINF2	NM_001099274.3	c.838A>G	p.Lys280Glu	missense_variant	6/9	ENST00000267415.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TINF2	ENST00000267415.12	c.838A>G	p.Lys280Glu	missense_variant	6/9	1	NM_001099274.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 04, 2023

Published functional studies demonstrate a damaging effect on telomere maintenance (Yang et al., 2011; Frescas et al., 2014; Jones et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21536674, 24449270, 18252230, 22211879, 27135879, 25525159, 36249522, 31383750, 34019708, 32300648) -

Dyskeratosis congenita, autosomal dominant 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2011

- -

Dyskeratosis congenita, autosomal dominant 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;T;.;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M;M;M;.;.;.
MutationTaster	Benign	0.86	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.48, 0.53
MutPred		0.69		Loss of methylation at K280 (P = 0.0033);Loss of methylation at K280 (P = 0.0033);Loss of methylation at K280 (P = 0.0033);.;.;.;
MVP		0.90
MPC		0.49
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.53
gMVP		0.62

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: rs121918543; hg19: chr14-24709848;