14-24239810-G-C

Variant names:

• chr14-24239810-G-C
• rs757192833
• NM_001099274.3:c.1343C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099274.3(TINF2):​c.1343C>G​(p.Ser448Cys) 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. 15/21 in silico tools predict 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. S448F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18947604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TINF2	NM_001099274.3	c.1343C>G	p.Ser448Cys	missense_variant	Exon 9 of 9	ENST00000267415.12	NP_001092744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TINF2	ENST00000267415.12	c.1343C>G	p.Ser448Cys	missense_variant	Exon 9 of 9	1	NM_001099274.3	ENSP00000267415.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita Uncertain:1

Apr 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 448 of the TINF2 protein (p.Ser448Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TINF2-related conditions. 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.066	T;T;.
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.26	N
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	.;N;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		0.99	D;D;D
Vest4		0.17
MutPred		0.17		Loss of phosphorylation at S448 (P = 0.0043);Loss of phosphorylation at S448 (P = 0.0043);.;
MVP		0.85
MPC		0.17
ClinPred		0.65	D
GERP RS		4.5
Varity_R		0.10
gMVP		0.20

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: rs757192833; hg19: chr14-24709016; COSMIC: COSV57469041; COSMIC: COSV57469041;