rs121918544

Positions:

• chr14-24240635-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_001099274.3(TINF2):​c.845G>A​(p.Arg282His) 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. R282C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.53

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24240636-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• PP5: Variant 14-24240635-C-T is Pathogenic according to our data. 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. Variant chr14-24240635-C-T is described in UniProt as null. Variant chr14-24240635-C-T is described in UniProt as null. Variant chr14-24240635-C-T is described in Lovd as [Pathogenic]. Variant chr14-24240635-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TINF2	NM_001099274.3	c.845G>A	p.Arg282His	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.845G>A	p.Arg282His	missense_variant	6/9	1	NM_001099274.3	ENSP00000267415	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 3 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Degerman lab, Umeå University	Nov 23, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.845G>A in Exon 6 of the TINF2 gene that results in the amino acid substitution p.Arg282His was identified. The observed variant has a minor allelefrequency of 0.000% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individualtools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for anindividual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 5625 as of 2022-12-31). The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage, Sharon A et al., 2008; Walne, Amanda J et al., 2008; Vulliamy, T et al., 2012). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 07, 2015	- -

Dyskeratosis congenita Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 11, 2023	This missense change has been observed in individuals with dyskeratosis congenita (PMID: 18252230, 18669893). Experimental studies have shown that this missense change affects TINF2 function (PMID: 21477109, 21536674, 29581185). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5625). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the TINF2 protein (p.Arg282His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg282 amino acid residue in TINF2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18669893, 19090550, 21199492, 23094712, 26859482, 29742735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2016	The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage SA et al. Am. J. Hum. Genet., 2008 Feb;82:501-9). Another study identified this mutation in an additional 14 individuals with DC and short telomeres; parental testing determined the majority of the identified mutations were de novo occurrences. In this cohort, individuals with this pathogenic mutation had clinically severe presentations, including individuals with Revesz syndrome and Hoyeraal-Hreidarsson syndrome (Walne AJ et al. Blood, 2008 Nov;112:3594-600). An in vitro functional study found this pathogenic mutation lead to telomere shortening, but did not affect telomerase activity, total levels of TERC, ,or cell proliferation; the authors propose telomere shortening may occur due to a defect in telomerase trafficking (Yang D et al. J. Biol. Chem., 2011 Jul;286:23022-30). Based on the supporting evidence, p.R282H is interpreted as a disease-causing mutation. -

Revesz syndrome;C3151445:Dyskeratosis congenita, autosomal dominant 3;C4551974:Dyskeratosis congenita, autosomal dominant 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 02, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 30, 2021

PS3, PS4_moderate, PM1, PM2_supporting, PP3 -

Revesz syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;T;.;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	2.0	M;M;M;.;.;.
MutationTaster	Benign	0.99	A;A;A;A;A;A
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	.;N;N;.;.;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D;D;.;.;D
Sift4G	Pathogenic	0.0	.;D;D;.;.;.
Polyphen		0.76	P;.;P;P;.;.
Vest4		0.59, 0.75
MutPred		0.78		Gain of catalytic residue at K280 (P = 0.001);Gain of catalytic residue at K280 (P = 0.001);Gain of catalytic residue at K280 (P = 0.001);.;.;.;
MVP		0.89
MPC		0.60
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.37
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918544; hg19: chr14-24709841; COSMIC: COSV104566597; COSMIC: COSV104566597;