rs104895235
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_001065.4(TNFRSF1A):c.287T>C(p.Leu96Pro) 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 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
5
8
6
Clinical Significance
Conservation
PhyloP100: 0.494
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 6 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_001065.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.903
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF1A | NM_001065.4 | c.287T>C | p.Leu96Pro | missense_variant | 3/10 | ENST00000162749.7 | |
TNFRSF1A | NM_001346091.2 | c.-38T>C | 5_prime_UTR_variant | 2/9 | |||
TNFRSF1A | NM_001346092.2 | c.-291T>C | 5_prime_UTR_variant | 3/11 | |||
TNFRSF1A | NR_144351.2 | n.549T>C | non_coding_transcript_exon_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF1A | ENST00000162749.7 | c.287T>C | p.Leu96Pro | 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: 1425172Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 705686
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1425172
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
705686
Gnomad4 AFR exome
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Gnomad4 AMR exome
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Gnomad4 ASJ exome
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Gnomad4 EAS 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: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2014 | The L96P variant has been reported previously, using alternate nomenclature, in a family with features of TRAPS, including fevers, abdominal pain, and urticaria (Dode et al., 2002). The L96P 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (N94I, H95L/Y) have been reported in the Human Gene Mutation Database in association with TNFRSF1A-related disorders (Stenson et al., 2009), supporting the functional importance of this region of the protein. The L96P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is moderately conserved across species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. - |
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
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;.;.
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;T;D;D
Sift4G
Uncertain
D;.;D;.;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at L100 (P = 0);Gain of catalytic residue at L100 (P = 0);Gain of catalytic residue at L100 (P = 0);Gain of catalytic residue at L100 (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