12-6334161-A-C

Variant names:

• chr12-6334161-A-C
• rs104895271
• NM_001065.4:c.123T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 10P and 6B. PM5 PP5_Very_Strong BP4 BS1_Supporting BS2

The NM_001065.4(TNFRSF1A):​c.123T>G​(p.Asp41Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. D41H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:3 O:1
• Conservation: PhyloP100: -2.29
• Publications: 19 publications found

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]

TNFRSF1A Gene-Disease associations (from GenCC):

• TNF receptor 1-associated periodic fever syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6334163-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 546694.
• PP5: Variant 12-6334161-A-C is Pathogenic according to our data. Variant chr12-6334161-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 97643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.064067245). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000237 (36/152142) while in subpopulation NFE AF = 0.000412 (28/68022). AF 95% confidence interval is 0.000292. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.123T>G	p.Asp41Glu	missense_variant	Exon 2 of 10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NR_144351.2	n.385T>G		non_coding_transcript_exon_variant	Exon 2 of 9
TNFRSF1A	NM_001346092.2	c.-455T>G		5_prime_UTR_variant	Exon 2 of 11		NP_001333021.1
TNFRSF1A	NM_001346091.2	c.-131-296T>G		intron_variant	Intron 1 of 8		NP_001333020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.123T>G	p.Asp41Glu	missense_variant	Exon 2 of 10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000163 AC: 41 AN: 250836 AF XY: 0.000162

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000336

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000280 AC: 410 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.000265 AC XY: 193 AN XY: 727240

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000354 AC: 394 AN: 1111994

Other (OTH) AF: 0.000132 AC: 8 AN: 60394

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74316

African (AFR) AF: 0.000121 AC: 5 AN: 41412

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000415 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS) Pathogenic:10 Other:1

Aug 15, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TNFRSF1A c.123T>G (p.Asp41Glu) missense variant, also known as D12E, has been reported in at least four studies in which it is found in a heterozygous state in at least nine individuals with familial periodic fever (FPF) with widely variable symptoms (D'Osualdo et al. 2006; Cantarini et al. 2009; Cantarini et al. 2013; Havla et al. 2013; Lachmann et al. 2014). In two of these affected individuals, the p.Asp41Glu variant was not detected in the parents and is reported as de novo (Cantarini et al. 2009; Cantarini et al. 2013) while Havla et al. (2013), report two unrelated probands with a family history of FPF-related symptoms. An additional individual with a clinical history of periodic fever was reported to carry the p.Asp41Glu variant in the heterozygous state and a missense variant in the MEFV gene in the homozygous status, and was diagnosed with familial Mediterranean fever, highlighting the extensive overlap in clinical manifestations between these two conditions (Gattorno et al. 2008). Of note, not all known genes associated with periodic fever were assessed in these affected individuals. Control data are unavailable for this variant, which is reported at a frequency of 0.00033 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Asp41Glu variant is classified as likely pathogenic for familial periodic fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Apr 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNFRSF1A c.123T>G (p.Asp41Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 250836 control chromosomes. The observed variant frequency is approximately 164-fold of the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF1A causing TNF receptor-associated periodic fever syndrome (TRAPS) phenotype (1e-06). c.123T>G has been observed in multiple individual(s) affected with TNF receptor-associated periodic fever syndrome (Havla_2013, DOsualdo_2006, Similuk_2022, Kong_2023, Cantarini_2013) and has also been shown to segregate with the disease (Havla_2013). Variant is associated with a milder phenotype in affected individuals (Cantarini_2013). These data indicate that the variant is likely to be associated with disease. Co-occurrence with another pathogenic variant has been reported (MEFV c.2040G>C, p.Met680Ile in homozygous state) for this variant. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 23745996, 24393624, 16508982, 18512793, 23322460, 38057357, 26598380, 30476936, 35753512, 33165748). ClinVar contains an entry for this variant (Variation ID: 97643). Based on the evidence outlined above, the variant was 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

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 41 of the TNFRSF1A protein (p.Asp41Glu). This variant is present in population databases (rs104895271, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with TNF receptor-associated periodic fever syndrome (TRAPS) (PMID: 16508982, 23322460, 24393624, 35753512). It has also been observed to segregate with disease in related individuals. This variant is also known as D12E. ClinVar contains an entry for this variant (Variation ID: 97643). 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) indicates that this missense variant is not expected to disrupt TNFRSF1A protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNFRSF1A function (PMID: 26598380). 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. -

Feb 16, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 moderate, PM6, PP1 moderate, PP4 supporting -

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Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Moderate, PM1, PM6 -

Oct 04, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Missense variants have been demonstrated to increase STAT-mTOR signalling (PMID: 26598380), however, as this protein homotrimerizes dominant negative is also a potential mechanism (PMID: 32380704). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Missense variants that do not impact a cysteine residue are well known to have incomplete penetrance (PMID: 32831641, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (44 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, and observed in multiple individuals or families with familial periodic fever, idiopathic recurrent acute pericarditis or TNF-receptor-associated periodic syndrome (TRAPS). In one of these individuals, segregation testing proved the variant was de novo (ClinVar, PMID: 23322460, PMID: 32831641, PMID: 23745996). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 02, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PS2_SUP,PM5_SUP,PP1 -

not provided Pathogenic:3 Uncertain:3

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNFRSF1A: PP1:Strong, PM2:Supporting, PS3:Supporting -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Jun 18, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis suggests that this missense variant does not alter protein structure/function; Also known as p.(D12E); This variant is associated with the following publications: (PMID: 32565720, 24393624, 23965844, 16508982, 18512793, 26299986, 29062244, 32199921, 32831641, 26992170, 26965498, 31589614, 26598380, 19917181, 23322460, 23745996, 34426522, 35753512, Subervie2024[Article], 30476936, Newsom2023[Abstract], 38589954) -

Apr 02, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TNFRSF1A c.123T>G; p.Asp41Glu variant (rs104895271), also published as D12E, is reported in the literature in several individuals affected with periodic fever or inflammatory syndromes (Bozgeyik 2020, Cantarini 2014, D'Osualdo 2006, Lachmann 2014). The variant is reported to segregate with disease in one family (Havla 2013) and developed de novo in another affected individual (Cantarini 2013). The variant is reported in the ClinVar database (Variation ID: 97643) and is listed in the European (non-Finnish) population with an allele frequency of 0.03% (41/128,538 alleles) in the Genome Aggregation Database. The aspartic acid at codon 41 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.541). Based on available information, this variant is considered to be likely pathogenic, but is associated with a mild phenotype and low penetrance. References: Bozgeyik E et al. Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics. Genomics. 2020 Jul;112(4):2755-2762. Cantarini L et al. The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up. Semin Arthritis Rheum. 2014 Jun;43(6):818-23. Cantarini L et al. Expanding spectrum of TNFRSF1A gene mutations among patients with idiopathic recurrent acute pericarditis. Intern Med J. 2013 Jun;43(6):725-7. 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. Havla J et al. Symptoms related to tumor necrosis factor receptor 1-associated periodic syndrome, multiple sclerosis, and severe rheumatoid arthritis in patients carrying the TNF receptor superfamily 1A D12E/p.Asp41Glu mutation. J Rheumatol. 2013 Mar;40(3):261-4. 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 Dec;73(12):2160-7. 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. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Apr 29, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammatory syndrome Pathogenic:1

Aug 08, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TNFRSF1A-related disorder Pathogenic:1

Aug 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TNFRSF1A c.123T>G variant is predicted to result in the amino acid substitution p.Asp41Glu. Of note, this variant is also referred to as D12E in the literature. This variant has been reported to be pathogenic in multiple patients with tumor necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) or with the autoimmune diseases multiple sclerosis and rheumatoid arthritis (Family 8, Proband, D'Osualdo et al. 2006. PubMed ID: 16508982; Cantarini et al. 2009. PubMed ID: 19917181; Havla et al. 2013. PubMed ID: 23322460; Cantarini et al. 2014. PubMed ID: 24393624; Lachmann et al. 2014. PubMed ID: 23965844). This variant has been reported to occur de novo (Cantarini et al. 2009. PubMed ID: 19917181) and has been identified in additional family members with clinical features (Havla et al. 2013. PubMed ID: 23322460). This variant has also been described as a low penetrance variant associated with mild or atypical disease presentations (D'Osualdo et al. 2006. PubMed ID: 16508982; Cantarini et al. 2014. PubMed ID: 24393624). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	0.019
DANN	Benign	0.82
DEOGEN2	Benign	0.19	T;T;T;.;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.64	T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.064	T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.46	N;.;.;N;.;.
PhyloP100		-2.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.090	N;N;N;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.92	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;.;T;.;T
Polyphen		0.0020	B;B;.;.;.;.
Vest4		0.045
MutPred		0.63		Gain of catalytic residue at P45 (P = 0.0448);Gain of catalytic residue at P45 (P = 0.0448);Gain of catalytic residue at P45 (P = 0.0448);Gain of catalytic residue at P45 (P = 0.0448);Gain of catalytic residue at P45 (P = 0.0448);Gain of catalytic residue at P45 (P = 0.0448);
MVP		0.99
MPC		0.55
ClinPred		0.55	D
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.92
Mutation Taster		=14/86	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104895271; hg19: chr12-6443327;