14-24240636-G-T

Variant names:

• chr14-24240636-G-T
• rs121918545
• NM_001099274.3:c.844C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001099274.3(TINF2):​c.844C>A​(p.Arg282Ser) 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. R282C) has been classified as Pathogenic.

• 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: 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 10 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 NM_001099274.3
• 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 ClinVar as [Pathogenic]. Clinvar id is 5627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 14-24240636-G-T is Pathogenic according to our data. Variant chr14-24240636-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 5626.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-24240636-G-T is described in UniProt as null. Variant chr14-24240636-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TINF2	NM_001099274.3	c.844C>A	p.Arg282Ser	missense_variant	Exon 6 of 9	ENST00000267415.12	NP_001092744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TINF2	ENST00000267415.12	c.844C>A	p.Arg282Ser	missense_variant	Exon 6 of 9	1	NM_001099274.3	ENSP00000267415.7

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

Dyskeratosis congenita, autosomal dominant 3 Pathogenic:1

Jul 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dyskeratosis congenita Pathogenic:1

Mar 03, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with serine at codon 282 of the TINF2 protein (p.Arg282Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in in individual(s) with dyskeratosis congenita (PMID: 18252230). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 5626). This variant has been reported to affect TINF2 protein function (PMID: 21536674). This variant disrupts the p.Arg282 amino acid residue in TINF2. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 18669893, 19090550, 21199492, 26859482, 29742735, 23094712). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dyskeratosis congenita, autosomal dominant 1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;T;.;.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	2.0	M;M;M;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.82	.;N;N;.;.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D;D;.;.;D
Sift4G	Pathogenic	0.0	.;D;D;.;.;.
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.71, 0.92
MutPred		0.79		Gain of catalytic residue at K280 (P = 0.0267);Gain of catalytic residue at K280 (P = 0.0267);Gain of catalytic residue at K280 (P = 0.0267);.;.;.;
MVP		0.94
MPC		0.46
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.42
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;