12-6333180-A-G

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.473-33T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 1,608,846 control chromosomes in the GnomAD database, including 314,795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 39057 hom., cov: 32)

Exomes 𝑓: 0.61 ( 275738 hom. )

Consequence

TNFRSF1A
NM_001065.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.364

Publications

42 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 (MetaRNN=9.108376E-7).

BP6

Variant 12-6333180-A-G is Benign according to our data. Variant chr12-6333180-A-G is described in ClinVar as Benign. ClinVar VariationId is 1166190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4 link	c.473-33T>C	intron_variant	Intron 4 of 9	ENST00000162749.7	NP_001056.1	P19438-1
TNFRSF1A	NM_001346091.2 link	c.149-33T>C	intron_variant	Intron 3 of 8		NP_001333020.1	P19438-2J9PH39
TNFRSF1A	NM_001346092.2 link	c.-105-33T>C	intron_variant	Intron 4 of 10		NP_001333021.1	P19438
TNFRSF1A	NR_144351.2 link	n.735-33T>C	intron_variant	Intron 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 link	c.473-33T>C		intron_variant	Intron 4 of 9	1	NM_001065.4	ENSP00000162749.2		P19438-1

Frequencies

GnomAD3 genomes

AF:

0.702

AC:

106731

AN:

151986

Hom.:

39001

Cov.:

show subpopulations

Gnomad AFR

AF:

0.914

Gnomad AMI

AF:

0.583

Gnomad AMR

AF:

0.723

Gnomad ASJ

AF:

0.674

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.687

Gnomad FIN

AF:

0.626

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.602

Gnomad OTH

AF:

0.694

GnomAD2 exomes

AF:

0.644

AC:

159487

AN:

247490

AF XY:

0.638

show subpopulations

Gnomad AFR exome

AF:

0.919

Gnomad AMR exome

AF:

0.728

Gnomad ASJ exome

AF:

0.673

Gnomad EAS exome

AF:

0.472

Gnomad FIN exome

AF:

0.621

Gnomad NFE exome

AF:

0.597

Gnomad OTH exome

AF:

0.644

GnomAD4 exome

AF:

0.611

AC:

890648

AN:

1456742

Hom.:

275738

Cov.:

AF XY:

0.613

AC XY:

444273

AN XY:

724756

show subpopulations

African (AFR)

AF:

0.926

AC:

30951

AN:

33412

American (AMR)

AF:

0.726

AC:

32249

AN:

44426

Ashkenazi Jewish (ASJ)

AF:

0.675

AC:

17604

AN:

26088

East Asian (EAS)

AF:

0.540

AC:

21418

AN:

39658

South Asian (SAS)

AF:

0.684

AC:

58870

AN:

86018

European-Finnish (FIN)

AF:

0.625

AC:

33306

AN:

53296

Middle Eastern (MID)

AF:

0.668

AC:

3844

AN:

5754

European-Non Finnish (NFE)

AF:

0.591

AC:

654790

AN:

1107886

Other (OTH)

AF:

0.625

AC:

37616

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

19694

39388

59081

78775

98469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17970

35940

53910

71880

89850

<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:

0.702

AC:

106847

AN:

152104

Hom.:

39057

Cov.:

AF XY:

0.704

AC XY:

52321

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.914

AC:

37939

AN:

41522

American (AMR)

AF:

0.723

AC:

11053

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.674

AC:

2336

AN:

3466

East Asian (EAS)

AF:

0.483

AC:

2488

AN:

5156

South Asian (SAS)

AF:

0.687

AC:

3315

AN:

4826

European-Finnish (FIN)

AF:

0.626

AC:

6627

AN:

10590

Middle Eastern (MID)

AF:

0.643

AC:

189

AN:

294

European-Non Finnish (NFE)

AF:

0.602

AC:

40909

AN:

67944

Other (OTH)

AF:

0.695

AC:

1459

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1540

3081

4621

6162

7702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

810

1620

2430

3240

4050

<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:

0.670

Hom.:

10441

Bravo

AF:

0.713

TwinsUK

AF:

0.602

AC:

2233

ALSPAC

AF:

0.582

AC:

2244

ESP6500AA

AF:

0.901

AC:

3969

ESP6500EA

AF:

0.598

AC:

5140

ExAC

AF:

0.641

AC:

77847

Asia WGS

AF:

0.635

AC:

2209

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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: 23505244) -

not specified

Benign:1

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 93% of patients studied by a panel of primary immunodeficiencies. Number of patients: 89. Only high quality variants are reported. -

TNF receptor-associated periodic fever syndrome (TRAPS)

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

0.25

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.0083

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.16

MetaRNN

Benign

9.1e-7

MetaSVM

Benign

-0.96

PhyloP100

-0.36

PROVEAN

Benign

1.1

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

ClinPred

0.040

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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