rs199422311

Variant names:

• chr14-24240633-G-A
• rs199422311
• NM_001099274.3:c.847C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-24240633-G-A
• chr14-24240633-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001099274.3(TINF2):​c.847C>T​(p.Pro283Ser) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P283H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 4.47
• Publications: 12 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Revesz syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 9 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24240632-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3576544.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 14-24240633-G-A is Pathogenic according to our data. Variant chr14-24240633-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TINF2	NM_001099274.3	c.847C>T	p.Pro283Ser	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.847C>T	p.Pro283Ser	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

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jun 01, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The P283S variant in the TINF2 gene was previously reported in association with dyskeratosis congenita in amale patient with aplastic anemia and overlapping features of Hoyeraal-Hreidarsson syndrome (Walne etal., 2008). It was not observed in approximately 6,200 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. P283S is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties.In addition, missense variants at the same codon (P283H/A), adjacent residues (R282H/C/S, T284A/K/R), and in nearby residues (E281K, L287P) have been reported in the Human Gene Mutation Database in associationwith dyskeratosis congenita (Stenson et al., 2014), supporting the functional importance of this region of theprotein. Given the available evidence, we interpret P283S as a pathogenic variant. -

TINF2-related disorder Pathogenic:1

Nov 28, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TINF2 c.847C>T variant is predicted to result in the amino acid substitution p.Pro283Ser. This variant was reported in two individuals with dyskeratosis congenita (Walne et al 2008. PubMed ID: 18669893; Table S1 Muramatsu H et al 2017. PubMed ID: 28102861). This variant resides in a mutational hotspot and other missense changes within the same amino acid, c.847C>G (p.Pro283Ala) and c.848C>A (p.Pro283His) have been reported in patients with dyskeratosis congenita (Walne et al 2008. PubMed ID: 18669893). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely 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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;.;T;.;.;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M;M;M;.;.;.
PhyloP100		4.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	.;N;N;.;.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;D;.;.;D
Sift4G	Pathogenic	0.0	.;D;D;.;.;.
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.50, 0.77
MutPred		0.80		Gain of catalytic residue at E281 (P = 0.0192);Gain of catalytic residue at E281 (P = 0.0192);Gain of catalytic residue at E281 (P = 0.0192);.;.;.;
MVP		0.94
MPC		0.58
ClinPred		0.98	D
GERP RS		5.2
PromoterAI		0.010	Neutral
Varity_R		0.40
gMVP		0.52
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199422311; hg19: chr14-24709839;