dbSNP rs5746026: TNFRSF1B:p.Glu232Lys (chr1-12193005-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001066.3(TNFRSF1B):c.694G>A(p.Glu232Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0335 in 1,614,192 control chromosomes in the GnomAD database, including 1,000 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.025 ( 55 hom., cov: 33)

Exomes 𝑓: 0.034 ( 945 hom. )

Consequence

TNFRSF1B
NM_001066.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.29

Publications

29 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=0.0024419427).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0255 (3883/152324) while in subpopulation EAS AF = 0.0394 (204/5182). AF 95% confidence interval is 0.0349. There are 55 homozygotes in GnomAd4. There are 1806 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 55 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3 link	c.694G>A	p.Glu232Lys	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.694G>A	p.Glu232Lys	missense_variant	Exon 6 of 10	1	NM_001066.3	ENSP00000365435.3	P20333-1
TNFRSF1B	ENST00000492361.1 link	n.683G>A		non_coding_transcript_exon_variant	Exon 5 of 9	1
TNFRSF1B	ENST00000489921.1 link	n.406G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0255

AC:

3885

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0130

Gnomad ASJ

AF:

0.0253

Gnomad EAS

AF:

0.0395

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.0241

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0352

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0272

AC:

6840

AN:

251286

AF XY:

0.0276

show subpopulations

Gnomad AFR exome

AF:

0.0142

Gnomad AMR exome

AF:

0.00850

Gnomad ASJ exome

AF:

0.0247

Gnomad EAS exome

AF:

0.0373

Gnomad FIN exome

AF:

0.0216

Gnomad NFE exome

AF:

0.0357

Gnomad OTH exome

AF:

0.0240

GnomAD4 exome

AF:

0.0343

AC:

50142

AN:

1461868

Hom.:

945

Cov.:

AF XY:

0.0338

AC XY:

24608

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0122

AC:

409

AN:

33480

American (AMR)

AF:

0.00939

AC:

420

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

660

AN:

26136

East Asian (EAS)

AF:

0.0408

AC:

1621

AN:

39700

South Asian (SAS)

AF:

0.0233

AC:

2008

AN:

86252

European-Finnish (FIN)

AF:

0.0228

AC:

1216

AN:

53420

Middle Eastern (MID)

AF:

0.00936

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0377

AC:

41873

AN:

1111994

Other (OTH)

AF:

0.0311

AC:

1881

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

3119

6238

9357

12476

15595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1600

3200

4800

6400

8000

<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:

0.0255

AC:

3883

AN:

152324

Hom.:

Cov.:

AF XY:

0.0243

AC XY:

1806

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0132

AC:

549

AN:

41570

American (AMR)

AF:

0.0129

AC:

198

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

AN:

3472

East Asian (EAS)

AF:

0.0394

AC:

204

AN:

5182

South Asian (SAS)

AF:

0.0232

AC:

112

AN:

4826

European-Finnish (FIN)

AF:

0.0241

AC:

256

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0351

AC:

2391

AN:

68028

Other (OTH)

AF:

0.0218

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

199

398

598

797

996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0315

Hom.:

351

Bravo

AF:

0.0239

TwinsUK

AF:

0.0415

AC:

154

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.0154

AC:

ESP6500EA

AF:

0.0344

AC:

296

ExAC

AF:

0.0287

AC:

3482

Asia WGS

AF:

0.0330

AC:

116

AN:

3478

EpiCase

AF:

0.0325

EpiControl

AF:

0.0302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.24

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.34

PhyloP100

1.3

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.39

REVEL

Benign

0.11

Sift

Benign

0.70

Sift4G

Uncertain

0.039

Polyphen

0.042

Vest4

0.041

MPC

0.40

ClinPred

0.0039

GERP RS

2.2

Varity_R

0.029

gMVP

0.55

Mutation Taster

=98/2

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

Computational scores

Splicing

Publications

Other links and lift over