Genetic Variant TINF2:p.Phe288Leu (chr14-24240618-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001099274.3(TINF2):c.862T>C(p.Phe288Leu) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. F288F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TINF2
NM_001099274.3 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 1.30

Publications

5 publications found

Variant links:

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]

TINF2 Gene-Disease associations (from GenCC):

dyskeratosis congenita, autosomal dominant 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Revesz syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, PanelApp Australia
pulmonary fibrosis
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
thyroid gland papillary carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TINF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001099274.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34159058).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099274.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TINF2	NM_001099274.3	MANE Select	c.862T>C	p.Phe288Leu	missense	Exon 6 of 9	NP_001092744.1	Q9BSI4-1
TINF2	NM_001363668.2		c.757T>C	p.Phe253Leu	missense	Exon 5 of 8	NP_001350597.1	B4DFJ1
TINF2	NM_012461.3		c.862T>C	p.Phe288Leu	missense	Exon 6 of 6	NP_036593.2	Q9BSI4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TINF2	ENST00000267415.12	TSL:1 MANE Select	c.862T>C	p.Phe288Leu	missense	Exon 6 of 9	ENSP00000267415.7	Q9BSI4-1
TINF2	ENST00000399423.8	TSL:1	c.862T>C	p.Phe288Leu	missense	Exon 6 of 6	ENSP00000382350.4	Q9BSI4-2
TINF2	ENST00000943625.1		c.862T>C	p.Phe288Leu	missense	Exon 6 of 9	ENSP00000613684.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aplastic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.066

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.66

M_CAP

Benign

0.040

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.3

PhyloP100

1.3

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.34

REVEL

Benign

0.17

Sift

Benign

0.66

Sift4G

Benign

0.49

Polyphen

0.0050

Vest4

0.12

MutPred

0.30

Gain of catalytic residue at N292 (P = 0.0061)

MVP

0.83

MPC

0.33

ClinPred

0.10

GERP RS

2.6

PromoterAI

-0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.10

gMVP

0.33

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over