12-6334108-C-T

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

Scores

12
6
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1O:1

Conservation

PhyloP100: 4.16
Variant links:
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 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
TNFRSF1ANM_001065.4 linkc.176G>A p.Cys59Tyr missense_variant Exon 2 of 10 ENST00000162749.7 NP_001056.1 P19438-1
TNFRSF1ANM_001346092.2 linkc.-402G>A 5_prime_UTR_variant Exon 2 of 11 NP_001333021.1 P19438
TNFRSF1ANM_001346091.2 linkc.-131-243G>A intron_variant Intron 1 of 8 NP_001333020.1 P19438-2J9PH39
TNFRSF1ANR_144351.2 linkn.438G>A non_coding_transcript_exon_variant Exon 2 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNFRSF1AENST00000162749.7 linkc.176G>A p.Cys59Tyr missense_variant Exon 2 of 10 1 NM_001065.4 ENSP00000162749.2 P19438-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
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 providedliterature onlyUnité médicale des maladies autoinflammatoires, CHRU Montpellier-- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 11, 2024This 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 submitterclinical testingMayo Clinic Laboratories, Mayo ClinicSep 14, 2023PP3, PM1, PM2, PM5, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;D;D;.;D;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.86
D;T;D;D;D;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Pathogenic
3.0
M;.;.;M;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-9.3
D;D;D;D;D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;.;D;.;D
Polyphen
1.0
D;D;.;.;.;.
Vest4
0.98
MutPred
0.88
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
0.98
MPC
2.0
ClinPred
1.0
D
GERP RS
4.0
Varity_R
1.0
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104895223; hg19: chr12-6443274; API