12-6333477-C-T

Variant names:

• chr12-6333477-C-T
• rs4149584
• NM_001065.4:c.362G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 4P and 13B. PM1 PM5 BP4_Strong BP6 BS1 BS2

The NM_001065.4(TNFRSF1A):​c.362G>A​(p.Arg121Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,613,480 control chromosomes in the GnomAD database, including 235 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R121P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 32)
  • Exomes 𝑓: 0.016 (223 hom.)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:9 O:1
• Conservation: PhyloP100: -1.46

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

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001065.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6333478-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070558786).
• BP6: Variant 12-6333477-C-T is Benign according to our data. Variant chr12-6333477-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217017.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Pathogenic=1, not_provided=1, Likely_benign=2, Benign=7}. Variant chr12-6333477-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.012 (1824/151614) while in subpopulation NFE AF = 0.0192 (1302/67788). AF 95% confidence interval is 0.0183. There are 12 homozygotes in GnomAd4. There are 852 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1824 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.362G>A	p.Arg121Gln	missense_variant	Exon 4 of 10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.38G>A	p.Arg13Gln	missense_variant	Exon 3 of 9		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.-216G>A		5_prime_UTR_variant	Exon 4 of 11		NP_001333021.1
TNFRSF1A	NR_144351.2	n.624G>A		non_coding_transcript_exon_variant	Exon 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.362G>A	p.Arg121Gln	missense_variant	Exon 4 of 10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1824 AN: 151496 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00334

Gnomad FIN AF: 0.00851

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0132 AC: 3312 AN: 251342 AF XY: 0.0131

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00902

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0160 AC: 23389 AN: 1461866 Hom.: 223 Cov.: 33 AF XY: 0.0159 AC XY: 11529 AN XY: 727228

Gnomad4 AFR exome AF: 0.00254 AC: 85 AN: 33480

Gnomad4 AMR exome AF: 0.0105 AC: 471 AN: 44724

Gnomad4 ASJ exome AF: 0.0185 AC: 484 AN: 26136

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39700

Gnomad4 SAS exome AF: 0.00398 AC: 343 AN: 86252

Gnomad4 FIN exome AF: 0.0124 AC: 661 AN: 53416

Gnomad4 NFE exome AF: 0.0183 AC: 20402 AN: 1111994

Gnomad4 Remaining exome AF: 0.0146 AC: 883 AN: 60396

GnomAD4 genome AF: 0.0120 AC: 1824 AN: 151614 Hom.: 12 Cov.: 32 AF XY: 0.0115 AC XY: 852 AN XY: 74078

Gnomad4 AFR AF: 0.00336 AC: 0.0033635 AN: 0.0033635

Gnomad4 AMR AF: 0.0115 AC: 0.011544 AN: 0.011544

Gnomad4 ASJ AF: 0.0205 AC: 0.0204965 AN: 0.0204965

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00355 AC: 0.00355203 AN: 0.00355203

Gnomad4 FIN AF: 0.00851 AC: 0.00850822 AN: 0.00850822

Gnomad4 NFE AF: 0.0192 AC: 0.0192069 AN: 0.0192069

Gnomad4 OTH AF: 0.0114 AC: 0.0114177 AN: 0.0114177

Alfa AF: 0.0180 Hom.: 107

Bravo AF: 0.0121

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0186 AC: 160

ExAC AF: 0.0140 AC: 1703

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0196

EpiControl AF: 0.0203

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS) Pathogenic:1 Uncertain:3 Benign:4 Other:1

Oct 18, 2019

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TNFRSF1A c.362G>A(p.(Arg121Gln) missense variant, also referred to as p.(Arg92Gln), is one of the most common variants associated with familial periodic fever (FPF) and has been identified in many individuals with a phenotype consistent with FPF (Aksentijevich et al. 2001; Ravet et al. 2006; Karatsourakis et al. 2014; Chandrakasan et al. 2014; Lachmann et al. 2014). The variant has been shown to segregate with disease with significantly reduced penetrance (Ravet et al. 2006; Lachmann et al. 2014). The highest frequency of this allele in the Genome Aggregation Database is 0.01987 in the European (non-Finnish) population including 29 homozygotes (version 2.1.1). Based on the conflicting evidence the c.362G>A(p.(Arg121Gln) variant is classified as a variant of uncertain significance for familial periodic fever. -

Sep 21, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 01-18-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2019

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNFRSF1A NM_001065.3 exon4 p.Arg121Gln (c.362G>A): This variant is well reported in the literature (alternate nomenclature p.Arg92Gln) and identified in several individuals with periodic fever syndrome (Aksentijevich 2001 PMID:11443543, D'Osualdo 2006 PMID:16508982, Ravet 2006 PMID:16569687, Pelagatti 2011 PMID:21225694, Cantarini 2013 PMID:23745996). However, in all literature reviewed, the phenotype of individuals with this variant is consistently reported as mild with several authors suggesting this is a low penetrance, variable mutation. At least 1 nonsegregation was also identified (Ravet 2006 PMID:16569687). This variant is present in 2% (2510/126556) of European alleles, including 24 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs4149584). This variant is present in ClinVar (Variation ID:217017). This variant amino acid Glutamine (Gln) is present in >15 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In vitro functional studies are conflicting and do not strongly predict that this variant will impact the protein (Aksentijevich 2001 PMID:11443543, D'Osualdo 2006 PMID:16508982, Greco 2015 PMID:25888769). However, these studies may not accurately represent in vivo biological function and further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Sep 07, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2013

UCLA Clinical Genomics Center, UCLA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2023

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Uncertain:2 Benign:3

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TNFRSF1A p.Arg121Gln variant has been reported multiple times in association with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (Ruiz-Ortiz_2017_PMID:28396659; Shinar_2012_PMID:22661645; Mühlenen_2015). The variant was identified in dbSNP (ID: rs4149584) LOVD 3.0 (classified as a VUS) and ClinVar (classified as benign by Invitae and ARUP Laboratories, as likely benign by CeGaT Praxis fuer Humangenetik Tuebingen, as uncertain significance by Laboratory for Molecular Medicine, GeneDx, EGL Genetic Diagnostics and Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, as likely pathogenic by Department of Genetics, Sultan Qaboos University Hospital, Oman and as pathogenic by UCLA Clinical Genomics Center, UCLA). The variant was identified in control databases in 3646 of 282618 chromosomes (29 homozygous) at a frequency of 0.0129 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2564 of 129036 chromosomes (freq: 0.01987), Ashkenazi Jewish in 184 of 10368 chromosomes (freq: 0.01775), Other in 125 of 7226 chromosomes (freq: 0.0173), European (Finnish) in 265 of 25094 chromosomes (freq: 0.01056), Latino in 319 of 35430 chromosomes (freq: 0.009004), South Asian in 111 of 30604 chromosomes (freq: 0.003627) and African in 78 of 24916 chromosomes (freq: 0.003131), but was not observed in the East Asian population. The p.Arg121Gln residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies provide inconsistent results regarding altered protein function (Aksentijevich_2001_PMID:11443543; Agulló_2015_PMID:26616867). This variant has been previously reported as pathogenic, however due to the high frequency in control populations may be a low penetrant or benign variant. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Sep 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNFRSF1A: BP4, BS1 -

Feb 07, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed together with a pathogenic variant in the MEFV gene in a patient with overlapping FMF and TRAPS phenotypes (Neocleous et al., 2016); also identified in patients heterozygous for a pathogenic variant in MEFV or NLRP3 at GeneDx; Variant frequency was not shown to differ between controls and the affected population (D'Osualdo et al., 2006); Functional studies have shown that this variant does not affect protein expression and localization or its interaction with TNF, but it results in a decrease of cellular inflammatory response (Lobito et al., 2006; Greco et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11443543, 21153350, 22799488, 29599418, 30407166, 16508982, 23117241, 21225694, 17234651, 22887853, 16684962, 21420073, 24286006, 20675856, 21565411, 25333069, 20876156, 19525953, 18287568, 23624563, 23894535, 23079392, 20576331, 21785959, 24393624, 25888769, 25866490, 16569687, 27884173, 26616867, 15657603, 27535533, 25936627, 23461592, 27332769, 28396659, 28361096, 28927886, 27990755, 26598380, 17949559, 17038455, 27994174, 29256170, 29950375, 31365210, 31028937, 31562507, 31422021, 32199921, 31586650, 32143951) -

not specified Benign:2

Feb 05, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg121Gln variant in TNFRSF1A is classified as likely benign because it has been identified in 1.8% (555/29600) of Ashkenazi Jewish chromosomes, including 235 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). ACMG/AMP Criteria applied: BS1. -

Oct 20, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNFRSF1A c.362G>A (p.Arg121Gln) results in a conservative amino acid change located in the TNFR/NGFR cysteine-rich region (IPR001368) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.013 in 282618 control chromosomes (gnomAD), including 29 homozygotes. The variant occurs predominantly at a frequency of 0.02 within the Non-Finnish European subpopulation in the gnomAD database, including 24 homozygotes. In a comprehensive characterization of the variant, Lobito_2006 demonstrated that the variant behaved similarly to the wild-type using various assays (e.g. cell surface expression, folding and association with wild-type receptors, secretion, trafficking, apoptosis inhibition). Eleven ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, five as uncertain significance, and five as benign. Based on the evidence outlined above, the variant was classified as benign. -

TNF receptor-associated periodic fever syndrome (TRAPS);C3553728:Multiple sclerosis, susceptibility to, 5 Uncertain:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNFRSF1A NM_001065.3 exon4 p.Arg121Gln (c.362G>A): This variant is well reported in the literature (alternate nomenclature p.Arg92Gln) and identified in several individuals with periodic fever syndrome (Aksentijevich 2001 PMID:11443543, D'Osualdo 2006 PMID:16508982, Ravet 2006 PMID:16569687, Pelagatti 2011 PMID:21225694, Cantarini 2013 PMID:23745996). However, in all literature reviewed, the phenotype of individuals with this variant is consistently reported as mild with several authors suggesting this is a low penetrance, variable mutation. At least 1 nonsegregation was also identified (Ravet 2006 PMID:16569687). This variant is present in 2% (2510/126556) of European alleles, including 24 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs4149584). This variant is present in ClinVar (Variation ID:217017). This variant amino acid Glutamine (Gln) is present in >15 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In vitro functional studies are conflicting and do not strongly predict that this variant will impact the protein (Aksentijevich 2001 PMID:11443543, D'Osualdo 2006 PMID:16508982, Greco 2015 PMID:25888769). However, these studies may not accurately represent in vivo biological function and further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain -

Autoinflammatory syndrome Uncertain:1

Apr 05, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	2.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;T;T;.;T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.76	T;T;T;T;T;T
MetaRNN	Benign	0.0071	T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.17	N;.;.;N;.;.
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.59	N;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.48	T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;.;T;.;D
Polyphen		0.68	P;P;.;.;.;.
Vest4		0.096
MPC		0.66
ClinPred		0.0054	T
GERP RS		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.91
Mutation Taster		=83/17	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4149584; hg19: chr12-6442643; COSMIC: COSV50610888; COSMIC: COSV50610888;