rs104895217

Positions:

• chr12-6334109-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001065.4(TNFRSF1A):​c.175T>C​(p.Cys59Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C59F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:2
• Conservation: PhyloP100: 4.94

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a strand (size 2) in uniprot entity TNR1A_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001065.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6334108-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 12-6334109-A-G is Pathogenic according to our data. Variant chr12-6334109-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6334109-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.175T>C	p.Cys59Arg	missense_variant	2/10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346092.2	c.-403T>C		5_prime_UTR_variant	2/11		NP_001333021.1
TNFRSF1A	NM_001346091.2	c.-131-244T>C		intron_variant			NP_001333020.1
TNFRSF1A	NR_144351.2	n.437T>C		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.175T>C	p.Cys59Arg	missense_variant	2/10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 02, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 11, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 59 of the TNFRSF1A protein (p.Cys59Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TNF receptor-associated periodic fever syndrome (TRAPS) (PMID: 10199409, 11722598, 22566169, 23965844). It has also been observed to segregate with disease in related individuals. This variant is also known as C30R. ClinVar contains an entry for this variant (Variation ID: 12337). 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) has been performed at Invitae 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: 16684962). This variant disrupts the p.Cys59 amino acid residue in TNFRSF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1144354, 10902757, 20576331). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 12-08-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2024

Published functional studies demonstrate a damaging effect with ER retention with affected surface labeling and internalization (PMID: 16684962); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19302049, 22566169, 10199409, 11722598, 16684962) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;.;D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T;T;T;T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.0	M;.;.;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-9.8	D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;.;D;.;D
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.98
MutPred		0.88		Gain of catalytic residue at K61 (P = 0);Gain of catalytic residue at K61 (P = 0);Gain of catalytic residue at K61 (P = 0);Gain of catalytic residue at K61 (P = 0);Gain of catalytic residue at K61 (P = 0);Gain of catalytic residue at K61 (P = 0);
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		4.0
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: rs104895217; hg19: chr12-6443275;