rs104895220
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_001065.4(TNFRSF1A):c.242G>T(p.Cys81Phe) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C81Y) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TNFRSF1A
NM_001065.4 missense
NM_001065.4 missense
Scores
12
4
3
Clinical Significance
Conservation
PhyloP100: 4.61
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 12 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain 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 chr12-6333818-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97668.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
?
Variant 12-6333817-C-A is Pathogenic according to our data. Variant chr12-6333817-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12338.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6333817-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF1A | NM_001065.4 | c.242G>T | p.Cys81Phe | missense_variant | 3/10 | ENST00000162749.7 | |
TNFRSF1A | NM_001346091.2 | c.-83G>T | 5_prime_UTR_variant | 2/9 | |||
TNFRSF1A | NM_001346092.2 | c.-336G>T | 5_prime_UTR_variant | 3/11 | |||
TNFRSF1A | NR_144351.2 | n.504G>T | non_coding_transcript_exon_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF1A | ENST00000162749.7 | c.242G>T | p.Cys81Phe | missense_variant | 3/10 | 1 | NM_001065.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1442984Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 716136
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1442984
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
716136
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
TNF receptor-associated periodic fever syndrome (TRAPS) Pathogenic:1Other:1
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 02, 1999 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2016 | The C81F variant has been published previosuly in association with autosomal dominant periodic fever (McDermott et al., 1999). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. C81F is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the TNFR-Cys1 repeat region that is conserved across species; this position forms a critical disulfide bond with the C62 residue (Aksentijevich et al., 2001). In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, multiple functional studies have shown that C81F disrupts normal TNFRSF1A function and localization (Todd et al., 2004; Lobito et al., 2006; Rebelo et al., 2009). Missense variants in the same residue (C81G/R/Y) and in nearby residues (T79M/K, C84R/Y/S, E85D) have been reported in the Human Gene Mutation Database in association with periodic fever (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic. - |
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;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D
Sift4G
Pathogenic
D;.;D;.;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at S86 (P = 0.0215);Gain of catalytic residue at S86 (P = 0.0215);Gain of catalytic residue at S86 (P = 0.0215);Gain of catalytic residue at S86 (P = 0.0215);.;
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