rs199740488
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001099274.3(TINF2):c.403C>T(p.Leu135Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,612,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
TINF2
NM_001099274.3 missense
NM_001099274.3 missense
Scores
5
9
Clinical Significance
Conservation
PhyloP100: 2.24
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.21864802).
BS2
?
High AC in GnomAd4 at 18 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TINF2 | NM_001099274.3 | c.403C>T | p.Leu135Phe | missense_variant | 4/9 | ENST00000267415.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TINF2 | ENST00000267415.12 | c.403C>T | p.Leu135Phe | missense_variant | 4/9 | 1 | NM_001099274.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000119 AC: 18AN: 151030Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000521 AC: 13AN: 249584Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135410
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GnomAD4 exome AF: 0.000109 AC: 159AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 81AN XY: 727246
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GnomAD4 genome ? AF: 0.000119 AC: 18AN: 151030Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9AN XY: 73794
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 27, 2021 | - - |
Dyskeratosis congenita Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 25, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 135 of the TINF2 protein (p.Leu135Phe). This variant is present in population databases (rs199740488, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TINF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 572348). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Revesz syndrome;C3151445:Dyskeratosis congenita, autosomal dominant 3;C4551974:Dyskeratosis congenita, autosomal dominant 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 20, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
Polyphen
D;.;D;D
Vest4
0.35, 0.34
MVP
0.58
MPC
0.58
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at