1-12193958-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001066.3(TNFRSF1B):c.791T>C(p.Leu264Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,712 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 18 hom. )

Consequence

TNFRSF1B
NM_001066.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.16

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009813637).

BP6

Variant 1-12193958-T-C is Benign according to our data. Variant chr1-12193958-T-C is described in ClinVar as [Benign]. Clinvar id is 780214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00668 (1018/152298) while in subpopulation AFR AF = 0.0234 (974/41556). AF 95% confidence interval is 0.0222. There are 13 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3 link	c.791T>C	p.Leu264Pro	missense_variant	Exon 7 of 10	ENST00000376259.7	NP_001057.1	P20333-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1B	ENST00000376259.7 link	c.791T>C	p.Leu264Pro	missense_variant	Exon 7 of 10	1	NM_001066.3	ENSP00000365435.3		P20333-1
TNFRSF1B	ENST00000492361.1 link	n.780T>C		non_coding_transcript_exon_variant	Exon 6 of 9	1

Frequencies

GnomAD3 genomes

AF:

0.00667

AC:

1015

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00189

AC:

475

AN:

251424

AF XY:

0.00141

show subpopulations

Gnomad AFR exome

AF:

0.0256

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000790

AC:

1154

AN:

1461414

Hom.:

Cov.:

AF XY:

0.000655

AC XY:

476

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.0265

AC:

888

AN:

33464

American (AMR)

AF:

0.00143

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000747

AC:

AN:

1111590

Other (OTH)

AF:

0.00181

AC:

109

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00668

AC:

1018

AN:

152298

Hom.:

Cov.:

AF XY:

0.00665

AC XY:

495

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0234

AC:

974

AN:

41556

American (AMR)

AF:

0.00163

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68044

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00266

Hom.:

Bravo

AF:

0.00720

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0204

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00225

AC:

273

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Dec 31, 2019

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

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0098

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.6

PhyloP100

1.2

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.23

Sift

Uncertain

0.0040

Sift4G

Benign

0.17

Polyphen

0.13

Vest4

0.61

MVP

0.33

MPC

0.63

ClinPred

0.020

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.66

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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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1-12193958-T-C

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