rs34751757

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001065.4(TNFRSF1A):c.269C>T(p.Thr90Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,583,076 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign 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. T90N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 2 hom. )

Consequence

TNFRSF1A
NM_001065.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.19

Publications

11 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: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_001065.4

BP4

Computational evidence support a benign effect (MetaRNN=0.037387967).

BP6

Variant 12-6333790-G-A is Benign according to our data. Variant chr12-6333790-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532185.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000657 (10/152294) while in subpopulation EAS AF = 0.00174 (9/5180). AF 95% confidence interval is 0.000906. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNFRSF1A	NM_001065.4 link	c.269C>T	p.Thr90Ile	missense_variant	Exon 3 of 10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NR_144351.2 link	n.531C>T		non_coding_transcript_exon_variant	Exon 3 of 9
TNFRSF1A	NM_001346091.2 link	c.-56C>T		5_prime_UTR_variant	Exon 2 of 9		NP_001333020.1
TNFRSF1A	NM_001346092.2 link	c.-309C>T		5_prime_UTR_variant	Exon 3 of 11		NP_001333021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 link	c.269C>T	p.Thr90Ile	missense_variant	Exon 3 of 10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000105

AC:

AN:

200708

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000115

Gnomad OTH exome

AF:

0.000192

GnomAD4 exome

AF:

0.000199

AC:

285

AN:

1430782

Hom.:

Cov.:

AF XY:

0.000196

AC XY:

139

AN XY:

709144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32874

American (AMR)

AF:

0.00

AC:

AN:

39572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25538

East Asian (EAS)

AF:

0.00738

AC:

282

AN:

38236

South Asian (SAS)

AF:

0.00

AC:

AN:

82570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095736

Other (OTH)

AF:

0.0000338

AC:

AN:

59246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41556

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000149

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS)

Uncertain:1Benign:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:1

Jan 12, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TNFRSF1A c.269C>T; p.Thr90Ile variant, also known as Thr61Ile, is published in the medical literature in several individuals with suspected TRAPS (Ida 2004, Ohmori 2014, Ueda 2016), but has also been published at a similar frequency in control individuals from the same ethnic group (Ida 2004, Ueda 2016). The variant is not listed in the ClinVar database, but is listed in the dbSNP variant database (rs34751757). The variant is described in the Genome Aggregation Database in 0.1 percent (20/13848 alleles) of the East Asian population. The threonine at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Additionally, another variant in the same amino acid, p.Thr90Pro, is published in an individual with suspected TRAPS and the variant appeared to segregate with disease. However, due to conflicting information, this variant cannot be classified with certainty. Pathogenic TNFRSF1A variants are associated with autosomal dominant periodic fever (MIM#142680). References: Ida H et al. A novel mutation (T61I) in the gene encoding tumour necrosis factor receptor superfamily 1A (TNFRSF1A) in a Japanese patient with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) associated with systemic lupus erythematosus. Rheumatology (Oxford). 2004 Oct;43(10):1292-9. Ohmori S et al. Inflammatory response to heparinoid and heparin in a patient with tumor necrosis factor receptor-associated periodic syndrome: the second case with a T61I mutation in the TNFRSF1A gene. J Dermatol. 2014 Dec;41(12):1112-3. Ueda N et al. Clinical and Genetic Features of Patients With TNFRSF1A Variants in Japan: Findings of a Nationwide Survey. Arthritis Rheumatol. 2016 Nov;68(11):2760-2771. Radhakrishna SM et al. Novel mutation identified in severe early-onset tumor necrosis factor receptor-associated periodic syndrome: a case report. BMC Pediatr. 2017 Apr 20;17(1):108. -

not specified

Benign:1

Aug 07, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TNFRSF1A c.269C>T (p.Thr90Ile) results in a non-conservative amino acid change located in the TNFR/NGFR cysteine-rich region (IPR001368) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 1583076 control chromosomes, predominantly at a frequency of 0.0067 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF1A causing TNF Receptor-Associated Periodic Fever Syndrome phenotype. c.269C>T has been reported in the literature in individuals affected with TNF Receptor-Associated Periodic Fever Syndrome as well as unaffected individuals (examples: Ida_2004 and Ueda_2016). These report(s) do not provide unequivocal conclusions about association of the variant with TNF Receptor-Associated Periodic Fever Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Ueda_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27332769, 15280569). ClinVar contains an entry for this variant (Variation ID: 532185). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;D;.;D;.

Eigen

Benign

0.027

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.70

T;T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.037

T;T;T;T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.4

M;.;M;.;.

PhyloP100

1.2

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.8

D;D;D;D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0040

D;T;T;T;T

Sift4G

Pathogenic

0.0

D;.;D;.;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.62

MVP

0.98

MPC

1.5

ClinPred

0.17

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.94

Mutation Taster

=14/86

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over