rs104895253

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_001065.4(TNFRSF1A):​c.250T>C​(p.Cys84Arg) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C84S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TNFRSF1A
NM_001065.4 missense

Scores

12
5
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 5.48
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]

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, 9 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 chr12-6333808-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 12-6333809-A-G is Pathogenic according to our data. Variant chr12-6333809-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97672.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6333809-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TNFRSF1ANM_001065.4 linkuse as main transcriptc.250T>C p.Cys84Arg missense_variant 3/10 ENST00000162749.7
TNFRSF1ANM_001346091.2 linkuse as main transcriptc.-75T>C 5_prime_UTR_variant 2/9
TNFRSF1ANM_001346092.2 linkuse as main transcriptc.-328T>C 5_prime_UTR_variant 3/11
TNFRSF1ANR_144351.2 linkuse as main transcriptn.512T>C non_coding_transcript_exon_variant 3/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNFRSF1AENST00000162749.7 linkuse as main transcriptc.250T>C p.Cys84Arg missense_variant 3/101 NM_001065.4 P1P19438-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 23, 2016- -
TNF receptor-associated periodic fever syndrome (TRAPS) Other:1
not provided, no classification providedliterature onlyUnité médicale des maladies autoinflammatoires, CHRU Montpellier-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D;D;.;D;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.68
T;T;T;T;T
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Pathogenic
3.4
M;.;M;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-10
D;D;D;D;D
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;.;D;.;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.98
MutPred
0.86
Gain of phosphorylation at S86 (P = 0.0617);Gain of phosphorylation at S86 (P = 0.0617);Gain of phosphorylation at S86 (P = 0.0617);Gain of phosphorylation at S86 (P = 0.0617);.;
MVP
1.0
MPC
2.1
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.99
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs104895253; hg19: chr12-6442975; API