rs104895235

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001065.4(TNFRSF1A):c.287T>C(p.Leu96Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

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

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 0.494

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

TNF receptor 1-associated periodic fever syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine, Illumina

TNFRSF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_001065.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4 link	c.287T>C	p.Leu96Pro	missense_variant	Exon 3 of 10	ENST00000162749.7	NP_001056.1	P19438-1
TNFRSF1A	NR_144351.2 link	n.549T>C		non_coding_transcript_exon_variant	Exon 3 of 9
TNFRSF1A	NM_001346091.2 link	c.-38T>C		5_prime_UTR_variant	Exon 2 of 9		NP_001333020.1	P19438-2J9PH39
TNFRSF1A	NM_001346092.2 link	c.-291T>C		5_prime_UTR_variant	Exon 3 of 11		NP_001333021.1	P19438

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 link	c.287T>C	p.Leu96Pro	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:

1425172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705686

African (AFR)

AF:

0.00

AC:

AN:

32776

American (AMR)

AF:

0.00

AC:

AN:

38628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25442

East Asian (EAS)

AF:

0.00

AC:

AN:

37950

South Asian (SAS)

AF:

0.00

AC:

AN:

82018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092556

Other (OTH)

AF:

0.00

AC:

AN:

59068

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 04, 2014

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The L96P variant has been reported previously, using alternate nomenclature, in a family with features of TRAPS, including fevers, abdominal pain, and urticaria (Dode et al., 2002). The L96P 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (N94I, H95L/Y) have been reported in the Human Gene Mutation Database in association with TNFRSF1A-related disorders (Stenson et al., 2009), supporting the functional importance of this region of the protein. The L96P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is moderately conserved across species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. -

TNF receptor-associated periodic fever syndrome (TRAPS)

Other:1

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

D;D;.;D;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.65

T;T;T;T;T

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Uncertain

0.025

MutationAssessor

Uncertain

2.8

M;.;M;.;.

PhyloP100

0.49

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.3

D;D;D;D;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.0060

D;D;T;D;D

Sift4G

Uncertain

0.012

D;.;D;.;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.57

MutPred

0.78

Gain of catalytic residue at L100 (P = 0);Gain of catalytic residue at L100 (P = 0);Gain of catalytic residue at L100 (P = 0);Gain of catalytic residue at L100 (P = 0);.;

MVP

0.99

MPC

1.9

ClinPred

0.75

GERP RS

1.2

Varity_R

0.94

gMVP

1.0

Mutation Taster

=11/89

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over