Variant rs5746026 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 55 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3 linkuse as main transcript	c.694G>A	p.Glu232Lys	missense_variant	6/10	ENST00000376259.7	NP_001057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1B	ENST00000376259.7 linkuse as main transcript	c.694G>A	p.Glu232Lys	missense_variant	6/10	1	NM_001066.3	ENSP00000365435	P1	P20333-1
TNFRSF1B	ENST00000492361.1 linkuse as main transcript	n.683G>A		non_coding_transcript_exon_variant	5/9	1
TNFRSF1B	ENST00000489921.1 linkuse as main transcript	n.406G>A		non_coding_transcript_exon_variant	3/3	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

GnomAD3 exomes

AF:

0.0272

AC:

6840

AN:

251286

Hom.:

107

AF XY:

0.0276

AC XY:

3754

AN XY:

135834

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 SAS exome

AF:

0.0231

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

Gnomad4 AFR exome

AF:

0.0122

Gnomad4 AMR exome

AF:

0.00939

Gnomad4 ASJ exome

AF:

0.0253

Gnomad4 EAS exome

AF:

0.0408

Gnomad4 SAS exome

AF:

0.0233

Gnomad4 FIN exome

AF:

0.0228

Gnomad4 NFE exome

AF:

0.0377

Gnomad4 OTH exome

AF:

0.0311

GnomAD4 genome

AF:

0.0255

AC:

3883

AN:

152324

Hom.:

Cov.:

AF XY:

0.0243

AC XY:

1806

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0132

Gnomad4 AMR

AF:

0.0129

Gnomad4 ASJ

AF:

0.0253

Gnomad4 EAS

AF:

0.0394

Gnomad4 SAS

AF:

0.0232

Gnomad4 FIN

AF:

0.0241

Gnomad4 NFE

AF:

0.0351

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.0313

Hom.:

183

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

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over