rs35653076

Positions:

• chr14-24242206-C-G
• chr14-24242206-C-T

Variant summary

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

The NM_001099274.3(TINF2):​c.127G>C​(p.Ala43Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A43D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.328

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=0.21938634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TINF2	NM_001099274.3	c.127G>C	p.Ala43Pro	missense_variant	1/9	ENST00000267415.12
TINF2	NM_001363668.2	c.127G>C	p.Ala43Pro	missense_variant	1/8
TINF2	NM_012461.3	c.127G>C	p.Ala43Pro	missense_variant	1/6
TINF2	XM_011536642.3	c.127G>C	p.Ala43Pro	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TINF2	ENST00000267415.12	c.127G>C	p.Ala43Pro	missense_variant	1/9	1	NM_001099274.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;T;.;.;.;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.078	N
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	.;N;N;.;.;N;D;D
REVEL	Benign	0.19
Sift	Benign	0.11	.;T;T;.;.;T;D;D
Sift4G	Uncertain	0.021	.;D;D;.;D;D;D;D
Polyphen		0.99	D;D;D;D;.;.;.;.
Vest4		0.47, 0.48, 0.54, 0.56, 0.51
MutPred		0.46		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP		0.52
MPC		2.3
ClinPred		0.65	D
GERP RS		0.029
Varity_R		0.70
gMVP		0.55

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: rs35653076; hg19: chr14-24711412;