rs121918545

Positions:

• chr14-24240636-G-A
• chr14-24240636-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000267415.12(TINF2):​c.844C>T​(p.Arg282Cys) variant causes a missense change. 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. R282H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TINF2 ENST00000267415.12 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 4.47

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000267415.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24240635-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 14-24240636-G-A is Pathogenic according to our data. Variant chr14-24240636-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24240636-G-A is described in Lovd as [Pathogenic]. Variant chr14-24240636-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TINF2	NM_001099274.3	c.844C>T	p.Arg282Cys	missense_variant	6/9	ENST00000267415.12	NP_001092744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TINF2	ENST00000267415.12	c.844C>T	p.Arg282Cys	missense_variant	6/9	1	NM_001099274.3	ENSP00000267415	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2024	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: 26859482, 21199492, 19090550, 29742735, 30523342, 23094712, 22211879, 27033759, 21659346, 18669893, 24168326, 23242325, 34573280, 32054657, 34522616) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2024	PP1, PP3, PM1, PM2, PM5, PS2, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2020	DNA sequence analysis of the TINF2 gene demonstrated a sequence change, c.844C>T, in exon 6 that results in an amino acid change, p.Arg282Cys. This sequence change has not been described in population databases (gnomAD, ExAC); however, it has been observed in several individuals with dyskeratosis congenita and aplastic anemia (PMIDs: 19090550, 21199492, 26859482, 18669893, 29742735, 23094712, 30523342). Additionally, several other sequence changes at the same location have been reported to be pathogenic (PMIDs: 18669893, 18252230, 21536674). The p.Arg282Cys change affects a highly conserved amino acid residue located in a domain of the TINF2 protein that is not known to be functional. The p.Arg282Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies have demonstrated that this sequence change does not impact protein binding in the shelterin complex, however the clinical significance of this finding is unknown at this time (PMID: 22211879). These collective evidences suggest that this sequence change is likely pathogenic. -

Dyskeratosis congenita, autosomal dominant 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000005627 ) and different missense changes at the same codon (p.Arg282His, p.Arg282Ser / ClinVar ID: VCV000005625 , VCV000005626 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -

Dyskeratosis congenita Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 30, 2018	The p.R282C pathogenic mutation (also known as c.844C>T), located in coding exon 6 of the TINF2 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported in multiple individuals with a clinical diagnosis of dyskeratosis congenita; most cases were reportedly de novo (paternity not confirmed); however, some individuals inherited the mutation from an affected parent (Walne AJ et al. Blood, 2008 Nov;112:3594-600; Du H et al. Medicine (Baltimore), 2018 May;97:e0724). This mutation was also described in two unrelated children with severe aplastic anemia (Du HY et al. Pediatr Blood Cancer, 2009 May;52:687). In addition, the most common TINF2 mutation, p.R282H, occurs at the same codon (Sasa GS et al. Clin. Genet., 2012 May;81:470-8). Based on the supporting evidence, p.R282C is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 12, 2021	- -

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	0.19
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;.;T;.;.;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	2.0	M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	.;N;N;.;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;D;D;.;.;D
Sift4G	Pathogenic	0.0	.;D;D;.;.;.
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.66, 0.75
MutPred		0.80		Gain of catalytic residue at K280 (P = 0.005);Gain of catalytic residue at K280 (P = 0.005);Gain of catalytic residue at K280 (P = 0.005);.;.;.;
MVP		0.95
MPC		0.71
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.27
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121918545; hg19: chr14-24709842;