12-6334108-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_001065.4(TNFRSF1A):c.176G>A(p.Cys59Tyr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C59F) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
TNFRSF1A
NM_001065.4 missense
NM_001065.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 4.16
Genes affected
TNFRSF1A (HGNC:11916): (TNF receptor superfamily member 1A) This gene encodes a member of the TNF receptor superfamily of proteins. The encoded receptor is found in membrane-bound and soluble forms that interact with membrane-bound and soluble forms, respectively, of its ligand, tumor necrosis factor alpha. Binding of membrane-bound tumor necrosis factor alpha to the membrane-bound receptor induces receptor trimerization and activation, which plays a role in cell survival, apoptosis, and inflammation. Proteolytic processing of the encoded receptor results in release of the soluble form of the receptor, which can interact with free tumor necrosis factor alpha to inhibit inflammation. Mutations in this gene underlie tumor necrosis factor receptor-associated periodic syndrome (TRAPS), characterized by fever, abdominal pain and other features. Mutations in this gene may also be associated with multiple sclerosis in human patients. [provided by RefSeq, Sep 2016]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
In a repeat TNFR-Cys 1 (size 39) in uniprot entity TNR1A_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_001065.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-6334108-C-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 12-6334108-C-T is Pathogenic according to our data. Variant chr12-6334108-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97652.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, not_provided=1}. Variant chr12-6334108-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TNFRSF1A | NM_001065.4 | c.176G>A | p.Cys59Tyr | missense_variant | Exon 2 of 10 | ENST00000162749.7 | NP_001056.1 | |
TNFRSF1A | NM_001346092.2 | c.-402G>A | 5_prime_UTR_variant | Exon 2 of 11 | NP_001333021.1 | |||
TNFRSF1A | NM_001346091.2 | c.-131-243G>A | intron_variant | Intron 1 of 8 | NP_001333020.1 | |||
TNFRSF1A | NR_144351.2 | n.438G>A | non_coding_transcript_exon_variant | Exon 2 of 9 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
TNF receptor-associated periodic fever syndrome (TRAPS) Uncertain:1Other:1
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 11, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 59 of the TNFRSF1A protein (p.Cys59Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TNF receptor-associated autoinflammatory syndrome (PMID: 15216558, 23965844, 33162992, 35640127). This variant is also known as p.Cys30Tyr. ClinVar contains an entry for this variant (Variation ID: 97652). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TNFRSF1A protein function with a positive predictive value of 80%. This variant disrupts the p.Cys59 amino acid residue in TNFRSF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23965844; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 14, 2023 | PP3, PM1, PM2, PM5, PS4_moderate - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;T;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;M;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;.;D;.;D
Polyphen
D;D;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at K61 (P = 0);Gain of catalytic residue at K61 (P = 0);Gain of catalytic residue at K61 (P = 0);Gain of catalytic residue at K61 (P = 0);Gain of catalytic residue at K61 (P = 0);Gain of catalytic residue at K61 (P = 0);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at