rs104895231
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP3_Strong
The NM_001065.4(TNFRSF1A):c.296G>A(p.Cys99Tyr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C99G) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes đť‘“: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TNFRSF1A
NM_001065.4 missense
NM_001065.4 missense
Scores
11
6
2
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001065.4
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr12-6333764-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.992
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF1A | NM_001065.4 | c.296G>A | p.Cys99Tyr | missense_variant | 3/10 | ENST00000162749.7 | |
TNFRSF1A | NM_001346091.2 | c.-29G>A | 5_prime_UTR_variant | 2/9 | |||
TNFRSF1A | NM_001346092.2 | c.-282G>A | 5_prime_UTR_variant | 3/11 | |||
TNFRSF1A | NR_144351.2 | n.558G>A | non_coding_transcript_exon_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF1A | ENST00000162749.7 | c.296G>A | p.Cys99Tyr | 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: 1422248Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 703998
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1422248
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
703998
Gnomad4 AFR exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link
Submissions by phenotype
TNF receptor-associated periodic fever syndrome (TRAPS) Other:1
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
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
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D
Sift4G
Uncertain
D;.;D;.;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at N94 (P = 0.0044);Gain of catalytic residue at N94 (P = 0.0044);Gain of catalytic residue at N94 (P = 0.0044);Gain of catalytic residue at N94 (P = 0.0044);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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