NM_001099274.3:c.847C>T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_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. P283A) has been classified as Pathogenic.
Frequency
Consequence
NM_001099274.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at