12-6333808-C-T

Variant names:

• chr12-6333808-C-T
• rs104895224
• NM_001065.4:c.251G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001346091.2(TNFRSF1A):​c.-74G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000694 in 1,439,902 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TNFRSF1A NM_001346091.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 4.61

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 12-6333808-C-T is Pathogenic according to our data. 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. Variant chr12-6333808-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.251G>A	p.Cys84Tyr	missense_variant	Exon 3 of 10	ENST00000162749.7	NP_001056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.251G>A	p.Cys84Tyr	missense_variant	Exon 3 of 10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1439902 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 714300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS) Pathogenic:2 Other:1

Oct 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 84 of the TNFRSF1A protein (p.Cys84Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tumor necrosis factor receptor-associated periodic fever syndrome (PMID: 16508982, 23965844; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys55Tyr. ClinVar contains an entry for this variant (Variation ID: 97673). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNFRSF1A protein function. Experimental studies have shown that this missense change affects TNFRSF1A function (PMID: 23117241). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 26, 2022

Eurofins-Biomnis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Pathogenic:1

Oct 16, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TNFRSF1A c.251G>A; p.Cys84Tyr variant (rs104895224), also known as Cys55Tyr or C55Y, has been published in the medical literature in several individuals with high penetrance TRAPS (D'Osulado 2006, Lachmann 2014, Papa 2017, Pelagatti 2011). Additionally, other variants in this codon (p.Cys84Arg, p.Cys84Ser) have been described in individuals with TRAPS (Rudofsky 2006, Jadoul 2001). The c.251G>A; p.Cys84Tyr variant has been described as a validated pathogenic variant by an expert group (see link to database below) and has also been described in the ClinVar database (Variation ID: 97673). The variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 84 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. The cysteine at this position is part of a cysteine-rich domain and is in the ligand-binding domain (Rebelo 2006). Functional analyses show this variant alters phenotype (Bachetti 2013, Pucino 2016). Considering available information, this variant is classified as pathogenic. References: Link to TNFRSF1A Infevers database: https://infevers.umai-montpellier.fr/web/search.php?n=2 Bachetti T et al. Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS). Ann Rheum Dis. 2013 Jun;72(6):1044-52. D'Osualdo A et al. Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis: pathogenetic and clinical implications. Arthritis Rheum. 2006 Mar;54(3):998-1008. Jadoul M et al. Autosomal-dominant periodic fever with AA amyloidosis: Novel mutation in tumor necrosis factor receptor 1 gene Rapid Communication. Kidney Int. 2001 May;59(5):1677-82. Lachmann HJ et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis. 2014;73:2160-2167 Papa R et al. A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. Orphanet J Rare Dis. 2017 Oct 18;12(1):167. Pelagatti MA et al. Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene. Arthritis Rheum. 2011 Apr;63(4):1141-50. Pucino V et al. Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome. J Leukoc Biol. 2016 May;99(5):761-9. Rebelo SL et al. Modeling of tumor necrosis factor receptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndrome indicates misfolding consistent with abnormal function. Arthritis Rheum. 2006 Aug;54(8):2674-87. Rudofsky G Jr et al. A nephrotic patient with tumour necrosis factor receptor-associated periodic syndrome, IgA nephropathy and CNS involvement. Nephrol Dial Transplant. 2006 Apr;21(4):1109-12. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;.;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.4	M;.;M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-9.7	D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;.;D;.;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.95
MutPred		0.88		Gain of phosphorylation at C84 (P = 0.0409);Gain of phosphorylation at C84 (P = 0.0409);Gain of phosphorylation at C84 (P = 0.0409);Gain of phosphorylation at C84 (P = 0.0409);.;
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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

Other links and lift over

dbSNP: rs104895224; hg19: chr12-6442974;