12-6334108-C-T

Position:

• chr12-6334108-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001065.4(TNFRSF1A):​c.176G>A​(p.Cys59Tyr) 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 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 4.16

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 11 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 12-6334108-C-T is Pathogenic according to our data. Variant chr12-6334108-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97652.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}. Variant chr12-6334108-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.176G>A	p.Cys59Tyr	missense_variant	2/10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346092.2	c.-402G>A		5_prime_UTR_variant	2/11		NP_001333021.1
TNFRSF1A	NM_001346091.2	c.-131-243G>A		intron_variant			NP_001333020.1
TNFRSF1A	NR_144351.2	n.438G>A		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.176G>A	p.Cys59Tyr	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: 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	Mar 27, 2017	This variant affects a cysteine residue located in the extracellular domain of the TNFRSF1A protein. Cysteine residues in this domain of TNFRSF1A are involved in the formation of disulfide bridges critical for subcellular protein trafficking (PMID: 27332769, 16684962). In addition, missense substitutions within the TNFRSF1A extracellular domain affecting cysteine residues are overrepresented in patients with periodic fever compared to the general population (gnomAD). In summary, this variant is absent in the population and has been observed in at least one affected individual. In addition, it is predicted to disrupt protein function. However, additional genetic or functional data are needed to further assess the clinical impact of this variant. For these reasons, this change has been classified as a Variant of Uncertain Significance. A different missense substitution at this codon (p.Cys59Arg) has been determined to be pathogenic (PMID: 23965844, Invitae). This suggests that the cysteine residue is critical for TNFRSF1A protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in the literature for at least one individual affected with TNF receptor-associated autoinflammatory syndrome (PMID: 15216558, 23965844). ClinVar contains an entry for this variant (Variation ID: 97652). This variant is also known as p.Cys30Tyr in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 59 of the TNFRSF1A protein (p.Cys59Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 14, 2023

PP3, PM1, PM2, PM5, PS4_moderate -

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	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;T;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.0	M;.;.;M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-9.3	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		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		4.0
Varity_R		1.0
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs104895223; hg19: chr12-6443274;