chr12-6334108-C-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_001065.4(TNFRSF1A):c.176G>C(p.Cys59Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 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. C59F) 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.176G>C | p.Cys59Ser | missense_variant | 2/10 | ENST00000162749.7 | |
TNFRSF1A | NM_001346092.2 | c.-402G>C | 5_prime_UTR_variant | 2/11 | |||
TNFRSF1A | NM_001346091.2 | c.-131-243G>C | intron_variant | ||||
TNFRSF1A | NR_144351.2 | n.438G>C | non_coding_transcript_exon_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF1A | ENST00000162749.7 | c.176G>C | p.Cys59Ser | missense_variant | 2/10 | 1 | NM_001065.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250404Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135464
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727248
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
TNF receptor-associated periodic fever syndrome (TRAPS) Pathogenic:2Other:1
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys59 amino acid residue in TNFRSF1A. Other variant(s) that disrupt this residue have been observed in individuals with TNFRSF1A-related conditions (PMID: 11722598, 15216558, 18408954, 10199409), which suggests that this may be a clinically significant amino acid residue. This variant has been reported to affect TNFRSF1A protein function (PMID: 16684962). This variant has been observed in several individuals and families affected with TNF receptor-associated periodic syndrome (TRAPS) (PMID: 10902757, 20576331, 11443543). This variant is also known as p.C30S in the literature. ClinVar contains an entry for this variant (Variation ID: 12342). This variant is present in population databases (rs104895223, ExAC 0.01%). This sequence change replaces cysteine with serine at codon 59 of the TNFRSF1A protein (p.Cys59Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2001 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at