rs4149646

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000366159.9(TNFRSF1A):n.2802G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 352,354 control chromosomes in the GnomAD database, including 521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 450 hom., cov: 33)

Exomes 𝑓: 0.0069 ( 71 hom. )

Consequence

TNFRSF1A
ENST00000366159.9 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0650

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 12-6328979-C-T is Benign according to our data. Variant chr12-6328979-C-T is described in ClinVar as Benign. ClinVar VariationId is 310101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4 link	c.*333G>A	3_prime_UTR_variant	Exon 10 of 10	ENST00000162749.7	NP_001056.1	P19438-1
TNFRSF1A	NR_144351.2 link	n.1889G>A	non_coding_transcript_exon_variant	Exon 9 of 9
TNFRSF1A	NM_001346091.2 link	c.*333G>A	3_prime_UTR_variant	Exon 9 of 9		NP_001333020.1	P19438-2J9PH39
TNFRSF1A	NM_001346092.2 link	c.*333G>A	3_prime_UTR_variant	Exon 11 of 11		NP_001333021.1	P19438

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 link	c.*333G>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_001065.4	ENSP00000162749.2		P19438-1

Frequencies

GnomAD3 genomes

AF:

0.0430

AC:

6543

AN:

152198

Hom.:

446

Cov.:

show subpopulations

Gnomad AFR

AF:

0.146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0207

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.0420

GnomAD4 exome

AF:

0.00686

AC:

1372

AN:

200038

Hom.:

Cov.:

AF XY:

0.00559

AC XY:

565

AN XY:

101034

show subpopulations

African (AFR)

AF:

0.141

AC:

852

AN:

6060

American (AMR)

AF:

0.0171

AC:

103

AN:

6010

Ashkenazi Jewish (ASJ)

AF:

0.00628

AC:

AN:

7798

East Asian (EAS)

AF:

0.00

AC:

AN:

18268

South Asian (SAS)

AF:

0.00

AC:

AN:

2208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16442

Middle Eastern (MID)

AF:

0.00370

AC:

AN:

1080

European-Non Finnish (NFE)

AF:

0.000856

AC:

110

AN:

128568

Other (OTH)

AF:

0.0187

AC:

254

AN:

13604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0430

AC:

6556

AN:

152316

Hom.:

450

Cov.:

AF XY:

0.0420

AC XY:

3131

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.146

AC:

6079

AN:

41538

American (AMR)

AF:

0.0206

AC:

315

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000661

AC:

AN:

68038

Other (OTH)

AF:

0.0416

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

292

583

875

1166

1458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0412

Hom.:

271

Bravo

AF:

0.0498

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS)

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.9

(source)

DANN

Benign

0.77

PhyloP100

-0.065

Mutation Taster

=100/0

polymorphism (auto)

(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