rs1061622

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001066.3(TNFRSF1B):c.587T>G(p.Met196Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,613,590 control chromosomes in the GnomAD database, including 43,833 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.22 ( 3657 hom., cov: 32)

Exomes 𝑓: 0.23 ( 40176 hom. )

Consequence

TNFRSF1B
NM_001066.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:3

Conservation

PhyloP100: -1.60

Publications

282 publications found

Variant links:

Genes affected

TNFRSF1B (HGNC:11917): (TNF receptor superfamily member 1B) The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein and TNF-receptor 1 form a heterocomplex that mediates the recruitment of two anti-apoptotic proteins, c-IAP1 and c-IAP2, which possess E3 ubiquitin ligase activity. The function of IAPs in TNF-receptor signalling is unknown, however, c-IAP1 is thought to potentiate TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2, which mediates anti-apoptotic signals. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways. [provided by RefSeq, Jul 2008]

TNFRSF1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025791824).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3 link	c.587T>G	p.Met196Arg	missense_variant	Exon 6 of 10	ENST00000376259.7	NP_001057.1	P20333-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFRSF1B	ENST00000376259.7 link	c.587T>G	p.Met196Arg	missense_variant	Exon 6 of 10	1	NM_001066.3	ENSP00000365435.3	P20333-1
TNFRSF1B	ENST00000492361.1 link	n.576T>G		non_coding_transcript_exon_variant	Exon 5 of 9	1
TNFRSF1B	ENST00000489921.1 link	n.299T>G		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32885

AN:

151996

Hom.:

3645

Cov.:

show subpopulations

Gnomad AFR

AF:

0.204

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.152

Gnomad ASJ

AF:

0.264

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.255

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.236

Gnomad OTH

AF:

0.207

GnomAD2 exomes

AF:

0.216

AC:

54148

AN:

250344

AF XY:

0.221

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.120

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.156

Gnomad FIN exome

AF:

0.225

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.232

AC:

338472

AN:

1461476

Hom.:

40176

Cov.:

AF XY:

0.233

AC XY:

169357

AN XY:

727046

show subpopulations

African (AFR)

AF:

0.210

AC:

7032

AN:

33476

American (AMR)

AF:

0.125

AC:

5580

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

7009

AN:

26128

East Asian (EAS)

AF:

0.140

AC:

5547

AN:

39688

South Asian (SAS)

AF:

0.259

AC:

22327

AN:

86234

European-Finnish (FIN)

AF:

0.232

AC:

12362

AN:

53374

Middle Eastern (MID)

AF:

0.259

AC:

1493

AN:

5766

European-Non Finnish (NFE)

AF:

0.237

AC:

263360

AN:

1111720

Other (OTH)

AF:

0.228

AC:

13762

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

14531

29062

43592

58123

72654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.216

AC:

32928

AN:

152114

Hom.:

3657

Cov.:

AF XY:

0.215

AC XY:

15954

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.204

AC:

8474

AN:

41482

American (AMR)

AF:

0.151

AC:

2314

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

914

AN:

3464

East Asian (EAS)

AF:

0.153

AC:

791

AN:

5176

South Asian (SAS)

AF:

0.255

AC:

1233

AN:

4832

European-Finnish (FIN)

AF:

0.232

AC:

2461

AN:

10590

Middle Eastern (MID)

AF:

0.259

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.236

AC:

16039

AN:

67964

Other (OTH)

AF:

0.205

AC:

433

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1351

2702

4054

5405

6756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.228

Hom.:

15243

Bravo

AF:

0.208

TwinsUK

AF:

0.241

AC:

894

ALSPAC

AF:

0.239

AC:

922

ESP6500AA

AF:

0.211

AC:

929

ESP6500EA

AF:

0.241

AC:

2069

ExAC

AF:

0.224

AC:

27145

Asia WGS

AF:

0.178

AC:

624

AN:

3478

EpiCase

AF:

0.233

EpiControl

AF:

0.234

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Susceptibility to severe coronavirus disease (COVID-19) due to high plasma levels of TNF, TNFR, and/or TNFR2

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

Differences in plasma levels of TNFR1 and TNFR2 according to genotypes -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

2.5

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.12

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.30

PhyloP100

-1.6

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.40

REVEL

Benign

0.044

Sift

Benign

0.26

Sift4G

Benign

0.29

Polyphen

0.0

Vest4

0.059

MPC

0.53

ClinPred

0.000027

GERP RS

-4.1

Varity_R

0.27

gMVP

0.68

Mutation Taster

=73/27

polymorphism (auto)

(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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rs1061622

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