dbSNP rs104895226: TNFRSF1A:p.Ser115Pro (chr12-6333496-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_001065.4(TNFRSF1A):c.343T>C(p.Ser115Pro) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S115F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TNFRSF1A
NM_001065.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.572

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001065.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNFRSF1A	NM_001065.4 link	c.343T>C	p.Ser115Pro	missense_variant	Exon 4 of 10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2 link	c.19T>C	p.Ser7Pro	missense_variant	Exon 3 of 9		NP_001333020.1
TNFRSF1A	NR_144351.2 link	n.605T>C		non_coding_transcript_exon_variant	Exon 4 of 9
TNFRSF1A	NM_001346092.2 link	c.-235T>C		5_prime_UTR_variant	Exon 4 of 11		NP_001333021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 link	c.343T>C	p.Ser115Pro	missense_variant	Exon 4 of 10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

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

Dec 22, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(S86P); This variant is associated with the following publications: (PMID: 11443543) -

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

0.87

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;D;D;.;D;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.77

T;T;T;T;T;T

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D

MetaSVM

Uncertain

0.082

MutationAssessor

Uncertain

2.7

M;.;.;M;.;.

PhyloP100

0.57

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.0

D;D;D;D;D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.011

D;D;D;D;D;D

Sift4G

Benign

0.079

T;T;.;D;.;D

Polyphen

1.0

D;D;.;.;.;.

Vest4

0.56

MutPred

0.73

Gain of catalytic residue at Q111 (P = 0);.;Gain of catalytic residue at Q111 (P = 0);Gain of catalytic residue at Q111 (P = 0);Gain of catalytic residue at Q111 (P = 0);.;

MVP

0.99

MPC

1.7

ClinPred

0.92

GERP RS

2.3

Varity_R

0.98

gMVP

1.0

Mutation Taster

=22/78

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