12-6333477-C-T

Position:

chr12-6333477-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM1PM5BP4_StrongBP6BS1BS2

The ENST00000162749.7(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. 13/20 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
ENST00000162749.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:9O:1

Conservation

PhyloP100: -1.46

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM1

In a disulfide_bond (size 20) in uniprot entity TNR1A_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in ENST00000162749.7

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: {Pathogenic=1, Benign=8, Uncertain_significance=6, Likely_benign=1, not_provided=1}. 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1824 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TNFRSF1A	NM_001065.4 linkuse as main transcript	c.362G>A	p.Arg121Gln	missense_variant	4/10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2 linkuse as main transcript	c.38G>A	p.Arg13Gln	missense_variant	3/9		NP_001333020.1
TNFRSF1A	NM_001346092.2 linkuse as main transcript	c.-216G>A		5_prime_UTR_variant	4/11		NP_001333021.1
TNFRSF1A	NR_144351.2 linkuse as main transcript	n.624G>A		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 linkuse as main transcript	c.362G>A	p.Arg121Gln	missense_variant	4/10	1	NM_001065.4	ENSP00000162749	P1	P19438-1

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1824

AN:

151496

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0132

AC:

3312

AN:

251342

Hom.:

AF XY:

0.0131

AC XY:

1785

AN XY:

135826

show subpopulations

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 SAS exome

AF:

0.00363

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.:

AF XY:

0.0159

AC XY:

11529

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00254

Gnomad4 AMR exome

AF:

0.0105

Gnomad4 ASJ exome

AF:

0.0185

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00398

Gnomad4 FIN exome

AF:

0.0124

Gnomad4 NFE exome

AF:

0.0183

Gnomad4 OTH exome

AF:

0.0146

GnomAD4 genome

AF:

0.0120

AC:

1824

AN:

151614

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

852

AN XY:

74078

show subpopulations

Gnomad4 AFR

AF:

0.00336

Gnomad4 AMR

AF:

0.0115

Gnomad4 ASJ

AF:

0.0205

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00355

Gnomad4 FIN

AF:

0.00851

Gnomad4 NFE

AF:

0.0192

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.0182

Hom.:

Bravo

AF:

0.0121

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0186

AC:

160

ExAC

AF:

0.0140

AC:

1703

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0196

EpiControl

AF:

0.0203

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS)

Pathogenic:1Uncertain:3Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 07, 2021	- -
Benign, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2023	- -
Pathogenic, flagged submission	clinical testing	UCLA Clinical Genomics Center, UCLA	Apr 02, 2013	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 21, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Sep 16, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 18, 2019	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. -

not provided

Uncertain:2Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	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) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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; MâˆšÂºhlenen_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; Agullâˆšâ‰¥_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. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TNFRSF1A: BP4, BS1, BS2 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 05, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 20, 2022	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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 27, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.24

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

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

MutationAssessor

Benign

0.17

N;.;.;N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.18

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

GERP RS

-3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.91

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

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

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