12-6330843-T-C

Variant names:

Variant summary

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

The NM_001065.4(TNFRSF1A):c.625+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,611,606 control chromosomes in the GnomAD database, including 123,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 10910 hom., cov: 30)

Exomes 𝑓: 0.39 ( 112398 hom. )

Consequence

TNFRSF1A
NM_001065.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:3B:11O:2

Conservation

PhyloP100: 0.172

Publications

218 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=-0.8).

BP6

Variant 12-6330843-T-C is Benign according to our data. Variant chr12-6330843-T-C is described in ClinVar as Benign. ClinVar VariationId is 37038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
TNFRSF1A	NM_001065.4 link	c.625+10A>G	intron_variant	Intron 6 of 9	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2 link	c.301+10A>G	intron_variant	Intron 5 of 8		NP_001333020.1
TNFRSF1A	NM_001346092.2 link	c.166+10A>G	intron_variant	Intron 7 of 10		NP_001333021.1
TNFRSF1A	NR_144351.2 link	n.814-132A>G	intron_variant	Intron 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 link	c.625+10A>G		intron_variant	Intron 6 of 9	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes

AF:

0.375

AC:

56939

AN:

151700

Hom.:

10912

Cov.:

show subpopulations

Gnomad AFR

AF:

0.348

Gnomad AMI

AF:

0.374

Gnomad AMR

AF:

0.354

Gnomad ASJ

AF:

0.413

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.301

Gnomad FIN

AF:

0.414

Gnomad MID

AF:

0.420

Gnomad NFE

AF:

0.412

Gnomad OTH

AF:

0.361

GnomAD2 exomes

AF:

0.361

AC:

90633

AN:

251114

AF XY:

0.361

show subpopulations

Gnomad AFR exome

AF:

0.347

Gnomad AMR exome

AF:

0.332

Gnomad ASJ exome

AF:

0.402

Gnomad EAS exome

AF:

0.141

Gnomad FIN exome

AF:

0.407

Gnomad NFE exome

AF:

0.408

Gnomad OTH exome

AF:

0.379

GnomAD4 exome

AF:

0.388

AC:

566393

AN:

1459786

Hom.:

112398

Cov.:

AF XY:

0.387

AC XY:

281181

AN XY:

726316

show subpopulations

African (AFR)

AF:

0.350

AC:

11710

AN:

33448

American (AMR)

AF:

0.327

AC:

14638

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.401

AC:

10481

AN:

26120

East Asian (EAS)

AF:

0.159

AC:

6314

AN:

39692

South Asian (SAS)

AF:

0.313

AC:

26987

AN:

86208

European-Finnish (FIN)

AF:

0.412

AC:

21969

AN:

53382

Middle Eastern (MID)

AF:

0.389

AC:

2175

AN:

5594

European-Non Finnish (NFE)

AF:

0.405

AC:

449664

AN:

1110320

Other (OTH)

AF:

0.372

AC:

22455

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

18416

36833

55249

73666

92082

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13670

27340

41010

54680

68350

<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:

0.375

AC:

56939

AN:

151820

Hom.:

10910

Cov.:

AF XY:

0.374

AC XY:

27718

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.348

AC:

14385

AN:

41368

American (AMR)

AF:

0.354

AC:

5390

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.413

AC:

1429

AN:

3464

East Asian (EAS)

AF:

0.136

AC:

702

AN:

5168

South Asian (SAS)

AF:

0.302

AC:

1451

AN:

4806

European-Finnish (FIN)

AF:

0.414

AC:

4361

AN:

10524

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.412

AC:

28008

AN:

67938

Other (OTH)

AF:

0.359

AC:

755

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1815

3629

5444

7258

9073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

552

1104

1656

2208

2760

<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:

0.394

Hom.:

52673

Bravo

AF:

0.368

Asia WGS

AF:

0.230

AC:

800

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, one paper claims association with MS -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 55% of patients studied by a panel of primary immunodeficiencies. Number of patients: 53. Only high quality variants are reported. -

not provided

Benign:3Other:1

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24174586, 22801493, 23624563) -

TNF receptor-associated periodic fever syndrome (TRAPS)

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

Associated with severe COVID-19 disease

Uncertain:1

Jul 01, 2023

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Susceptibility to severe coronavirus disease (COVID-19)

Uncertain:1

Feb 09, 2021

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Susceptibility to severe coronavirus disease (COVID-19) due to high plasma levels of TNF, TNFR, and/or TNFR6

Uncertain:1

Aug 07, 2021

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

NA -

Autoinflammatory syndrome

Benign:1

Jan 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Multiple sclerosis, susceptibility to, 5

Other:1

Aug 23, 2012

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

0.17

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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