chr12-6329900-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001065.4(TNFRSF1A):c.935G>A(p.Arg312Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,576,896 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. R312T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

TNFRSF1A
NM_001065.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:6

Conservation

PhyloP100: -0.110

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052860975).

BP6

Variant 12-6329900-C-T is Benign according to our data. Variant chr12-6329900-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378735.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0011 (167/152360) while in subpopulation AFR AF = 0.0031 (129/41590). AF 95% confidence interval is 0.00267. There are 2 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 167 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNFRSF1A	NM_001065.4 link	c.935G>A	p.Arg312Lys	missense_variant	Exon 9 of 10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2 link	c.611G>A	p.Arg204Lys	missense_variant	Exon 8 of 9		NP_001333020.1
TNFRSF1A	NM_001346092.2 link	c.476G>A	p.Arg159Lys	missense_variant	Exon 10 of 11		NP_001333021.1
TNFRSF1A	NR_144351.2 link	n.1123G>A		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 link	c.935G>A	p.Arg312Lys	missense_variant	Exon 9 of 10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000401

AC:

AN:

187008

AF XY:

0.000339

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.000594

Gnomad ASJ exome

AF:

0.00134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000179

Gnomad OTH exome

AF:

0.000200

GnomAD4 exome

AF:

0.000267

AC:

381

AN:

1424536

Hom.:

Cov.:

AF XY:

0.000258

AC XY:

182

AN XY:

705550

show subpopulations

African (AFR)

AF:

0.00342

AC:

112

AN:

32704

American (AMR)

AF:

0.000551

AC:

AN:

38094

Ashkenazi Jewish (ASJ)

AF:

0.00122

AC:

AN:

25498

East Asian (EAS)

AF:

0.00

AC:

AN:

37758

South Asian (SAS)

AF:

0.00

AC:

AN:

82664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50794

Middle Eastern (MID)

AF:

0.00420

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.000143

AC:

156

AN:

1092394

Other (OTH)

AF:

0.000628

AC:

AN:

58916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00110

AC:

167

AN:

152360

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00310

AC:

129

AN:

41590

American (AMR)

AF:

0.00118

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000452

Hom.:

Bravo

AF:

0.00126

ESP6500AA

AF:

0.00274

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000449

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

May 12, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28814775) -

Mar 10, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TNFRSF1A c.935G>A; p.Arg312Lys variant (rs200900510) is reported in the medical literature in an individual with Behcet disease (Burillo-Sanz 2017). The variant is reported in the ClinVar database (Variation ID: 378735) and is listed in the African population with an allele frequency of 0.35% (69/19,970 alleles, including 1 homozygote) in the Genome Aggregation Database. The arginine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Additionally, there are few known pathogenic variants in this region of the protein (Lobito 2011). Based on this and the increased population frequency in the African population, it is unlikely that this is a high penetrance pathogenic variant. However, we cannot rule out the possibility that this is a low penetrance variant without additional information. Therefore, considering available information, this variant is classified as a variant of uncertain significance. References: Burillo-Sanz S et al. Mutational profile of rare variants in inflammasome-related genes in Behcet disease: A Next Generation Sequencing approach. Sci Rep. 2017 Aug 16;7(1):8453. Lobito AA et al. Disease causing mutations in the TNF and TNFR superfamilies: Focus on molecular mechanisms driving disease. Trends Mol Med. 2011 Sep;17(9):494-505. -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TNFRSF1A: BP4, BS1 -

TNF receptor-associated periodic fever syndrome (TRAPS)

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Behcet disease

Pathogenic:1

Feb 22, 2017

Department of Immunology, Hospital Universitario Virgen del Rocio

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

- -

not specified

Benign:1

Apr 22, 2025

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.935G>A (p.Arg312Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 187008 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American 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.935G>A has been observed in individual(s) affected with Bechet Disease (Burillo-Sanz_2017) and Idiopathic Chronic Pancreatitis (Sofia_2016). These report(s) do not provide unequivocal conclusions about association of the variant with TNF Receptor-Associated Periodic Fever Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28814775, 27264265). ClinVar contains an entry for this variant (Variation ID: 378735). Based on the evidence outlined above, the variant was classified as likely benign. -

Autoinflammatory syndrome

Benign:1

Jan 29, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

7.1

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.43

T;T

M_CAP

Benign

0.068

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.9

L;.

PhyloP100

-0.11

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.010

N;N

REVEL

Benign

0.24

Sift

Benign

0.50

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.0030

B;B

Vest4

0.11

MVP

0.69

MPC

0.59

ClinPred

0.0012

GERP RS

2.7

Varity_R

0.13

gMVP

0.25

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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