rs121918544
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_001099274.3(TINF2):c.845G>A(p.Arg282His) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282C) has been classified as Pathogenic.
Frequency
Consequence
NM_001099274.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TINF2 | NM_001099274.3 | c.845G>A | p.Arg282His | missense_variant | 6/9 | ENST00000267415.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TINF2 | ENST00000267415.12 | c.845G>A | p.Arg282His | missense_variant | 6/9 | 1 | NM_001099274.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Dyskeratosis congenita, autosomal dominant 3 Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Degerman lab, Umeå University | Nov 23, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 07, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Heterozygous Missense variant c.845G>A in Exon 6 of the TINF2 gene that results in the amino acid substitution p.Arg282His was identified. The observed variant has a minor allelefrequency of 0.000% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individualtools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for anindividual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 5625 as of 2022-12-31). The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage, Sharon A et al., 2008; Walne, Amanda J et al., 2008; Vulliamy, T et al., 2012). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. - |
Dyskeratosis congenita Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 11, 2023 | This missense change has been observed in individuals with dyskeratosis congenita (PMID: 18252230, 18669893). Experimental studies have shown that this missense change affects TINF2 function (PMID: 21477109, 21536674, 29581185). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 5625). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the TINF2 protein (p.Arg282His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg282 amino acid residue in TINF2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18669893, 19090550, 21199492, 23094712, 26859482, 29742735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2016 | The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage SA et al. Am. J. Hum. Genet., 2008 Feb;82:501-9). Another study identified this mutation in an additional 14 individuals with DC and short telomeres; parental testing determined the majority of the identified mutations were de novo occurrences. In this cohort, individuals with this pathogenic mutation had clinically severe presentations, including individuals with Revesz syndrome and Hoyeraal-Hreidarsson syndrome (Walne AJ et al. Blood, 2008 Nov;112:3594-600). An in vitro functional study found this pathogenic mutation lead to telomere shortening, but did not affect telomerase activity, total levels of TERC, ,or cell proliferation; the authors propose telomere shortening may occur due to a defect in telomerase trafficking (Yang D et al. J. Biol. Chem., 2011 Jul;286:23022-30). Based on the supporting evidence, p.R282H is interpreted as a disease-causing mutation. - |
Revesz syndrome;C3151445:Dyskeratosis congenita, autosomal dominant 3;C4551974:Dyskeratosis congenita, autosomal dominant 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 02, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 30, 2021 | PS3, PS4_moderate, PM1, PM2_supporting, PP3 - |
Revesz syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at