12-6333764-A-G

Variant names:

• chr12-6333764-A-G
• rs104895228
• NM_001065.4:c.295T>C

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.295T>C​(p.Cys99Arg) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C99G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• 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 chr12-6333764-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 12-6333764-A-G is Pathogenic according to our data. Variant chr12-6333764-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6333764-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.295T>C	p.Cys99Arg	missense_variant	Exon 3 of 10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.-30T>C		5_prime_UTR_variant	Exon 2 of 9		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.-283T>C		5_prime_UTR_variant	Exon 3 of 11		NP_001333021.1
TNFRSF1A	NR_144351.2	n.557T>C		non_coding_transcript_exon_variant	Exon 3 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.295T>C	p.Cys99Arg	missense_variant	Exon 3 of 10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS) Pathogenic:2 Other:1

Feb 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 99 of the TNFRSF1A protein (p.Cys99Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tumor necrosis factor receptor–associated periodic syndrome (TRAPS) (PMID: 11817598). In at least one individual the variant was observed to be de novo. This variant is also known as Cys70Arg. ClinVar contains an entry for this variant (Variation ID: 97686). 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. This variant disrupts the p.Cys99 amino acid residue in TNFRSF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11239851, 13130484, 14610673, 23894535, 26078218, 31216807). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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Suma Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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not provided Pathogenic:2

Feb 06, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(C70R); This variant is associated with the following publications: (PMID: 14610673, 26078218, 23894535, 31216807, 13130484, 11239851, 33131906, Agarwal2023[Case_report], 33715002, 11443543, 11817598) -

Jun 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D;.;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.67	T;T;T;T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.4	M;.;M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-9.5	D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;.;D;.;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.98
MutPred		0.86		Gain of catalytic residue at L96 (P = 0.0021);Gain of catalytic residue at L96 (P = 0.0021);Gain of catalytic residue at L96 (P = 0.0021);Gain of catalytic residue at L96 (P = 0.0021);.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
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: rs104895228; hg19: chr12-6442930;