rs104895230
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_001065.4(TNFRSF1A):c.173G>T(p.Cys58Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. C58Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_001065.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF1A | NM_001065.4 | c.173G>T | p.Cys58Phe | missense_variant | 2/10 | ENST00000162749.7 | |
TNFRSF1A | NM_001346092.2 | c.-405G>T | 5_prime_UTR_variant | 2/11 | |||
TNFRSF1A | NM_001346091.2 | c.-131-246G>T | intron_variant | ||||
TNFRSF1A | NR_144351.2 | n.435G>T | non_coding_transcript_exon_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF1A | ENST00000162749.7 | c.173G>T | p.Cys58Phe | missense_variant | 2/10 | 1 | NM_001065.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727246
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
TNF receptor-associated periodic fever syndrome (TRAPS) Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 09, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys58 amino acid residue in TNFRSF1A. Other variant(s) that disrupt this residue have been observed in individuals with TNFRSF1A-related conditions (PMID: 11700162, 19541728, 20532935), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNFRSF1A protein function. ClinVar contains an entry for this variant (Variation ID: 97651). This variant is also known as C29F. This missense change has been observed in individuals with clinical features of necrosis factor receptor-associated periodic syndrome (PMID: 11700162, 23965844; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 58 of the TNFRSF1A protein (p.Cys58Phe). - |
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at