rs104895220

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_001065.4(TNFRSF1A):c.242G>T(p.Cys81Phe) 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. C81R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TNFRSF1A
NM_001065.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 4.61

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a disulfide_bond (size 19) in uniprot entity TNR1A_HUMAN there are 16 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 chr12-6333818-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 12-6333817-C-A is Pathogenic according to our data. Variant chr12-6333817-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12338.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6333817-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4 link	c.242G>T	p.Cys81Phe	missense_variant	Exon 3 of 10	ENST00000162749.7	NP_001056.1	P19438-1
TNFRSF1A	NM_001346091.2 link	c.-83G>T		5_prime_UTR_variant	Exon 2 of 9		NP_001333020.1	P19438-2J9PH39
TNFRSF1A	NM_001346092.2 link	c.-336G>T		5_prime_UTR_variant	Exon 3 of 11		NP_001333021.1	P19438
TNFRSF1A	NR_144351.2 link	n.504G>T		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 link	c.242G>T	p.Cys81Phe	missense_variant	Exon 3 of 10	1	NM_001065.4	ENSP00000162749.2		P19438-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1442984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716136

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS)

Pathogenic:1Other:1

Apr 02, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Aug 10, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The C81F variant has been published previosuly in association with autosomal dominant periodic fever (McDermott et al., 1999). 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. C81F is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the TNFR-Cys1 repeat region that is conserved across species; this position forms a critical disulfide bond with the C62 residue (Aksentijevich et al., 2001). In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, multiple functional studies have shown that C81F disrupts normal TNFRSF1A function and localization (Todd et al., 2004; Lobito et al., 2006; Rebelo et al., 2009). Missense variants in the same residue (C81G/R/Y) and in nearby residues (T79M/K, C84R/Y/S, E85D) have been reported in the Human Gene Mutation Database in association with periodic fever (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;D;.;D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.77

T;T;T;T;T

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.0

M;.;M;.;.

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-9.6

D;D;D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;.;D;.;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.98

MutPred

0.88

Gain of catalytic residue at S86 (P = 0.0215);Gain of catalytic residue at S86 (P = 0.0215);Gain of catalytic residue at S86 (P = 0.0215);Gain of catalytic residue at S86 (P = 0.0215);.;

MVP

0.99

MPC

1.9

ClinPred

1.0

GERP RS

5.0

Varity_R

1.0

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

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

Other links and lift over