12-6333794-A-G

Position:

• chr12-6333794-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5

The NM_001065.4(TNFRSF1A):​c.265T>C​(p.Phe89Leu) 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F89S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 5.48

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 15 ACMG points.

• PS1: Transcript NM_001065.4 (TNFRSF1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a disulfide_bond (size 15) in uniprot entity TNR1A_HUMAN there are 20 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 chr12-6333793-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 12-6333794-A-G is Pathogenic according to our data. Variant chr12-6333794-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97676.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}. Variant chr12-6333794-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.265T>C	p.Phe89Leu	missense_variant	3/10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.-60T>C		5_prime_UTR_variant	2/9		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.-313T>C		5_prime_UTR_variant	3/11		NP_001333021.1
TNFRSF1A	NR_144351.2	n.527T>C		non_coding_transcript_exon_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.265T>C	p.Phe89Leu	missense_variant	3/10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2023	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: 21420073). ClinVar contains an entry for this variant (Variation ID: 97676). This missense change has been observed in individuals with clinical features of TNFRSF1A-related conditions (PMID: 21420073, 23965844; Invitae). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the TNFRSF1A protein (p.Phe89Leu). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2016

The F89L variant has been published previously in association with TRAPS (Lachmann et al., 2014). Additionally, other publications have reported this variant as F60L, arising from both a c.264 C>G and a c.267 A>G nucleotide change (Aganna et al., 2003; Dinc et al., 2005). While these papers may be reporting the same F60L variant caused by separate nucleotide changes, they did not include information necessary for us to determine the cause of these nomenclature discrepancies. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. F89L is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved; however, in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that F89L increases TNF-stimulated c-Rel activity (Nedjai et al., 2011). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.0	M;.;M;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0060	D;D;D;D;D
Sift4G	Uncertain	0.010	D;.;D;.;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.79
MutPred		0.85		Gain of catalytic residue at N94 (P = 0.0064);Gain of catalytic residue at N94 (P = 0.0064);Gain of catalytic residue at N94 (P = 0.0064);Gain of catalytic residue at N94 (P = 0.0064);.;
MVP		0.93
MPC		1.6
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.99

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: rs104895245; hg19: chr12-6442960; COSMIC: COSV99370020; COSMIC: COSV99370020;