Submissions for variant NM_001065.4(TNFRSF1A):c.194-14G>A

gnomAD frequency: 0.00016  dbSNP: rs104895241

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494570	SCV000582219	uncertain significance	not provided	2021-11-30	criteria provided, single submitter	clinical testing	Published previously in association with TRAPS; however, the variant was also observed in unaffected family members and in an individual who had a remittance of symptoms (Aksentijevich et al., 2001; D'Osualdo et al., 2006; Stojanov et al., 2008; Gattorno et al., 2008); Functional studies have shown this variant creates a cryptic splice acceptor site, resulting in an insertion of four additional amino acids (Aksentijevich et al., 2001); Reported previously using alternate nomenclature (c.193-14 G>A); This variant is associated with the following publications: (PMID: 12352631, 16508982, 25525159, 15228182, 19541728, 12209523, 18180277, 19877056, 13130484, 33181346, 11443543, 18512793, 28166811)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000083907	SCV001494846	uncertain significance	TNF receptor-associated periodic fever syndrome (TRAPS)	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the TNFRSF1A gene. It does not directly change the encoded amino acid sequence of the TNFRSF1A protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 4 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs104895241, gnomAD 0.03%). This variant has been observed in individual(s) with tumor necrosis factor receptor–associated periodic syndrome (PMID: 11443543, 18180277). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 97654). Studies have shown that this variant results in the activation of a cryptic splice site in intron 3 (PMID: 11443543). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000494570	SCV002545001	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	TNFRSF1A: PS4:Moderate, PM4:Supporting, PS3:Supporting
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083907	SCV000116017	not provided	TNF receptor-associated periodic fever syndrome (TRAPS)		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV003407471	SCV004113207	uncertain significance	TNFRSF1A-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The TNFRSF1A c.194-14G>A variant is predicted to interfere with splicing. This variant is predicted to interfere with normal spicing by activating a cryptic splice acceptor (SpliceAI, Jaganathan K, et al. 2019. PubMed ID: 30661751). In vitro functional analyses supported this prediction, indicating that aberrant splicing results in the addition of four amino acids (variant described as c.193-14G>A, Aksentijevich et al 2001. PubMed ID: 11443543). This variant was reported in five patients from two families with TNF receptor-associated periodic syndrome (TRAPS) (Aksentijevich et al 2001. PubMed ID: 11443543). It is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect this variant may be pathogenic, at this time the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.