rs104895271

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PP5_Very_StrongBP4

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

TNFRSF1A
NM_001065.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15U:3O:1

Conservation

PhyloP100: -2.29

Variant links:

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 links:

TNFRSF1A (HGNC:):

TNFRSF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a chain Tumor necrosis factor-binding protein 1 (size 160) in uniprot entity TNR1A_HUMAN there are 73 pathogenic changes around while only 1 benign (99%) in NM_001065.4

PP5

Variant 12-6334161-A-C is Pathogenic according to our data. Variant chr12-6334161-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4 linkuse as main transcript	c.123T>G	p.Asp41Glu	missense_variant	2/10	ENST00000162749.7	NP_001056.1	P19438-1
TNFRSF1A	NM_001346092.2 linkuse as main transcript	c.-455T>G		5_prime_UTR_variant	2/11		NP_001333021.1	P19438
TNFRSF1A	NM_001346091.2 linkuse as main transcript	c.-131-296T>G		intron_variant			NP_001333020.1	P19438-2J9PH39
TNFRSF1A	NR_144351.2 linkuse as main transcript	n.385T>G		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 linkuse as main transcript	c.123T>G	p.Asp41Glu	missense_variant	2/10	1	NM_001065.4	ENSP00000162749.2		P19438-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000163

AC:

AN:

250836

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135636

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000265

AC XY:

193

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000354

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000237

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000448

Hom.:

Bravo

AF:

0.000215

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS)

Pathogenic:9Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	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). 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 15, 2018	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. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 16, 2021	ACMG classification criteria: PS4 moderate, PM6, PP1 moderate, PP4 supporting -
Likely pathogenic, no assertion criteria provided	research	Genomics And Bioinformatics Analysis Resource, Columbia University	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 01, 2024	PS3_Moderate, PM1, PM6 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 02, 2024	Criteria applied: PS4,PS2_SUP,PM5_SUP,PP1 -

not provided

Pathogenic:3Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 02, 2021	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TNFRSF1A: PP1:Strong, PM2:Supporting, PS3:Supporting -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2024	In silico analysis indicates 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) -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2016

- -

Autoinflammatory syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 08, 2021

- -

TNFRSF1A-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2024

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

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

LIST_S2

Benign

0.64

T;T;T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.064

T;T;T;T;T;T

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

0.46

N;.;.;N;.;.

PrimateAI

Benign

0.33

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

GERP RS

-7.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over